CN1253554A

CN1253554A - Heterocyclic compounds and their use for inhibiting 'beta'-amyloid peptide

Info

Publication number: CN1253554A
Application number: CN98802875A
Authority: CN
Inventors: E·D·托尔瑟特; W·J·波特; J·S·尼森; L·H·拉蒂默; J·E·奥迪尔; J·J·德罗斯特
Original assignee: Elan Pharmaceuticals LLC; Eli Lilly and Co
Current assignee: Elan Pharmaceuticals LLC; Eli Lilly and Co
Priority date: 1997-02-28
Filing date: 1998-02-27
Publication date: 2000-05-17
Also published as: YU7998A; AR011164A1; IL130851A0; HUP0001293A3; TR199902071T2; ZA981627B; KR20000075767A; CO4920244A1; EP0968198A1; EA199900778A1; HUP0001293A1; HRP980093A2; NO994016D0; CA2278674A1; PE59399A1; WO1998038177A1; NZ336613A; AU6662298A; ID22873A; NO994016L

Abstract

Disclosed are compounds which inhibit beta -amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits beta -amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

Description

The purposes of heterogeneous ring compound and inhibition beta amyloid peptide thereof

The background of invention invention field

The present invention relates to suppress the compound that the cell beta amyloid peptide discharges and/or it is synthetic and therefore have treatment Alzheimer effectiveness.Reference

Following publication, patent and patent application are in this application with the subscript numeric reference:

¹Glenner etc., " Alzheimer: novel cerebrovascular amyloid

The first report of the characterized of purifying " Biochem.Biophys.Res.

Commun.，120：885-890(1984)。

²Glenner etc., " polypeptide marker of Alzheimer and diagnosis thereof are used

On the way ", the United States Patent (USP) the 4th, 666,829 of authorizing on May 19th, 1987

Number.

³Selkoe, " molecular pathology of Alzheimer ", Neuron,

6：487-498(1991)。

⁴Goate etc. are " in the amyloid precursor of family's Alzheimer

The separation of missense mutation ", Nature, 349:704-706 (1990).

⁵Chartier-Harlan etc., " close by amyloid beta precursor protein gene

The Alzheimer of the early onset thereof that numeral 717 sudden changes cause ",

Nature，353：844-846(1989)。

⁶Murrell etc., " the amylaceous egg relevant with the heredity Alzheimer

Sudden change in the Cynanchum glaucescens body protein ", Science, 254:97-99 (1991).

⁷Mullan etc. " may in the amyloid beta N-terminal in the app gene

The pathogenic mutation of Alzheimer ", Nature Genet.,

1：345-347(1992)。

⁸Schenk etc., " monitoring the method and composition of solvable beta amyloid peptide ",

In on May 11st, 1994 disclosed international patent application WO is disclosed

No. 94/10569.

⁹Selkoe, " amyloid and Alzheimer ", Scientific

American, 2-8 page or leaf, in November, 1991.

¹⁰??Tetrahedron?Letters，34(48)，7685(1993)。

¹¹Losse etc., Tetrahedron, 27:1423-1434 (1971).

¹²Citron etc., " the amyloid beta in the familial Alzheimer

The precursor protein sudden change increases the generation of beta-protein ", Nature, 360:672-674

(1992)。

¹³Hansen etc. " heavily check and further exploitation measurement cell growth and/or thin

The dyeing process accurately and fast that born of the same parents kill and wound ", J.Immun.Meth.,

119：203-210(1989)。

All above publications, patent and patent application all are attached to herein as a reference by reference, its degree and each independent publication, patent or patent application show specially and individually all be attached to by reference the same as a reference herein.The situation of this area

Alzheimer (AD) is a kind of degeneration encephalopathic, and its Clinical symptoms is to remember, the carrying out property forfeiture of cognition, reasoning, judgement and emotional stability, and causes degree of depth spirit to be degenerated (mental deterioration) gradually, finally causes death.AD is the very common reason of carrying out property mental disorder (dementia) among the elderly, it is believed that in the U.S. to be the 4th dead main medical reasons.In worldwide ethnic group and ethnic group, observe AD, and be the present and following main public health problem.Estimating at present only should disease just influence about two to three million peoples in the U.S..AD can not cure at present.The unknown at present therapy of effectively preventing AD or reversing its symptom and the course of disease.

The brain of suffering from the individuality of AD shows the characteristic infringement, is called (or amyloid) spot in old age, amyloid angiopathy (amyloid deposits in blood vessel) and neurofibrillary tangles.A large amount of these infringements, particularly amyloid spot and neurofibrillary tangles are generally found in several zones to the important human brain of memory and cognitive function in suffering from the patient of AD.These infringements of the minority of more limited anatomic distribution are also found in the most of the elderlys' that do not have clinical AD brain.The feature of amyloid spot and amyloid angiopathy is also for having the individual brain of the 21st pair of karyomit(e) trisomy (mongolism) and having the heredity cerebral hemorrhage (HCHWA-D) of Dutch type amyloidosis.At present, making a definite diagnosis usually of AD need be observed above-mentioned infringement in suffering from dead person's cerebral tissue of this disease or in the little biopsy samples of cerebral tissue that takes out under few situation during the invasive neurosurgery.

The amyloid spot of AD and above-mentioned other disease and blood vessel amyloid deposition (amyloid angiopathy) distinctive main chemical composition, be about 39-43 amino acid whose about 4.2 kilodaltons (kD) albumen, be called beta amyloid peptide (β AP), or be sometimes referred to as A β, A β P or β/A4.Glenner etc. ¹Purifying beta amyloid peptide at first, and partial amino-acid series is provided.In United States Patent (USP) the 4th, 666,829 ²In the data of separation method and preceding 28 amino acid whose sequences have been described.

Molecular biology and albumen chemical analysis show, beta amyloid peptide is the small segment of much bigger precursor protein (APP), and APP is normally produced by the cell in many tissues of various animals (comprising the people).The understanding of gene structure to coding APP is verified, and beta amyloid peptide, is produced as peptide fragment from the APP cutting-out by proteolytic enzyme.Downcut and it be not immediately clear as amyloid spot sedimentary accurate biochemical mechanism cerebral tissue and cerebrovascular wall and meningovascular wall subsequently from APP about the beta amyloid peptide fragment.

The evidence of several respects shows, carrying out property beta amyloid peptide brain is deposited in the AD morbidity and plays basic role, and can the several years or many decades occur prior to cognitive symptom.Referring to for example Selkoe ³The evidence of most important one side is to find in the several families of the AD with heredity decision (familial) form, the missense dna mutation of amino acid 717 can be found in influenced member in 770 amino acid isotypes of APP, and does not find that in unaffected member (Goate etc. 4; Chartier-Harlan etc. 5 and Murrell etc. 6), this mutant form is called as Sweden's varient.Reported the Methionin of in a family of Swede, finding in 1992 ⁵⁹⁵-methionine(Met) ⁵⁹⁶Sport l-asparagine ⁵⁹⁵-leucine ⁵⁹⁶Two sudden change (Mulan etc. of (with reference to 695 isotypes) ⁷).Genetic linkage analysis is verified, and other sudden change of some in these sudden changes and the app gene is the specific molecular reason of influenced member AD in this class family.In addition, identified a reason that sports beta amyloid peptide storage disorders HCHWA-D of amino acid 693 in 770 amino acid isotypes of APP, and in other cases, in the patient of some non-HCHWA-D, produce the phenotype of similar AD to the variation of glycine by L-Ala in amino acid 692 places.Prove that based on these sudden changes of APP in the AD case of heredity and the discovery of other sudden change the segmental deposition subsequently of the change of APP and its beta amyloid peptide can cause AD.

Although making progress aspect the potential mechanism of understanding AD and other beta amyloid peptide relative disease, but still need exploitation to treat the method and composition of described disease.It is desirable to, described methods of treatment is preferably based on and can suppresses beta amyloid peptide release and/or its synthetic medicine in the body.

Summary of the invention

The present invention relates to find a compounds, this compounds suppresses that beta amyloid peptide discharges and/or it is synthetic, so they are used in the patient that prevention AD among the easy trouble AD patient and/or treatment suffer from AD, to suppress the further deterioration of its state of an illness.This compounds with above-mentioned character is by defining with following formula I:

A-B-C

Wherein A is selected from:

R wherein ¹Be selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic radical;

Z is selected from:

(a) have formula-CX ' X " C (O)-group, wherein X ' is hydrogen, hydroxyl or fluorine; X " be

Hydrogen, hydroxyl or fluorine, or X ' and X " form the oxo base together;

(b) have formula-T-CX ' X " C (O)-group, wherein T be selected from oxygen, sulphur and-NR ³,

R wherein ³Be hydrogen, acyl group, alkyl, aryl or heteroaryl; X ' is hydrogen or fluorine,

X " be hydrogen, hydroxyl or fluorine, or X ' and X " form the oxo base together; And

(c) have formula-CX ' X "-T-C (O)-group, wherein T be selected from oxygen, sulphur and-NR ³,

X " be hydrogen, hydroxyl or fluorine, or X ' and X " form the oxo base together;

R ²Be selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, cycloalkyl, aryl, heteroaryl and heterocyclic radical;

R ⁶Be selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, cycloalkyl, aryl, heteroaryl and heterocyclic radical;

M is 0 or 1 integer, and

P is 0 or 1 integer;

T ' is selected from R ¹Be connected in-CX ' X "-on covalent linkage, oxygen, sulphur and-NR ³, R wherein ³Be hydrogen, acyl group, alkyl, aryl or heteroaryl;

W and X are independently selected from-(CR ⁷R ⁷) _q-, oxygen, sulphur and-NR ⁸, wherein q is 1 or 2 integer, and each R ⁷And R ⁸Be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl group, acyloxy, carboxyl, carboxylicesters and heterocyclic radical, in addition, when q is 2, the R on each described carbon atom ⁷Group can randomly combine with described ethylidene and form aryl, heteroaryl, heterocyclic radical or cycloalkyl, and prerequisite is when unsaturated, all the other R on each carbon atom ⁷Group participates in that this is unsaturated;

And another prerequisite is that when W was oxygen, X was not an oxygen;

X ' is hydrogen, hydroxyl or fluorine, X " be hydrogen, hydroxyl or fluorine, or X ' and X " form the oxo base together;

R ⁴Be selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical; And

T ' is selected from R ¹Be connected in-CX ' X "-covalent linkage, oxygen, sulphur and-NR ³, R wherein ³Be hydrogen, acyl group, alkyl, aryl or heteroaryl;

R ⁴Be selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical;

B is selected from:

R wherein ⁵Be selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical;

And another prerequisite is that when W was oxygen, X was not an oxygen;

W and X are independently selected from-(CR ⁷R ⁷) _q-, oxygen, sulphur and-NR ⁸, wherein q is 1 or 2 integer, and each R ⁷And R ⁸Be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl group, acyloxy and heterocyclic radical, in addition, when q is 2, the R on each described carbon atom ⁷Group can randomly combine with described ethylidene and form aryl, heteroaryl, heterocyclic radical or cycloalkyl, and prerequisite is when unsaturated, all the other R on each carbon atom ⁷Group participates in that this is unsaturated;

(iv) when A be above definition formula (ii) or formula (iii) the time, B also can be the covalent linkage that connects A and C;

C is selected from: (i)-C (O) Y or-C (S) Y

Wherein Y is selected from:

(a) alkyl or cycloalkyl,

(b) substituted alkyl, prerequisite are that the replacement on the described substituted alkyl does not comprise alpha-halogen alkyl, α-diazonium alkyl, α-OC (O) alkyl or α-OC (O) aryl,

(c) alkoxyl group or thio alkoxy,

(d) substituted alkoxy or replacement thio alkoxy,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic radical,

(i)-NR ' R "; wherein R ' and R " be independently selected from hydrogen, alkyl, alkenyl, alkynyl group, substituted alkyl, the substituted alkenyl base, the substituted alkenyl base, cycloalkyl, aryl, heteroaryl, heterocyclic radical, wherein R ' or R " one of be hydroxyl or alkoxyl group; and R ' and R " in conjunction with forming a cyclic group, described cyclic group has 2-8 carbon atom, can randomly contain 1-2 other heteroatoms and (be selected from oxygen, sulphur and nitrogen), and can randomly use one or more alkyl, alkoxyl group or carboxyalkyl replace

(j)-NHSO ₂-R ⁸, R wherein ⁸Be selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, cycloalkyl, aryl, heteroaryl and heterocyclic radical,

(k)-NR ⁹NR ¹⁰R ¹⁰, R wherein ⁹Be hydrogen or alkyl, and each R ¹⁰Be independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl base, cycloalkyl, aryl, heteroaryl, heterocyclic radical, and

(l)-ONR ⁹[C (O) O] _zR ¹⁰, wherein z is 0 or 1, R ⁹And R ¹⁰As above-mentioned definition; (ii)-CR ¹¹R ¹¹Y '

Each R wherein ¹¹Be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical, and Y ' be selected from hydroxyl, alkoxyl group, amino, thiol, substituted alkoxy, thio alkoxy, replacement thio alkoxy ,-OC (O) R ⁹,-SSR ⁹With-SSC (O) R ⁹, R wherein ⁹Be selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical; And

Wherein A forms heterocyclic radical with-C=N-, this heterocyclic radical can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, each in this ring structure can randomly replace with being selected from following 1-4 substituting group again: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, aryl, heteroaryl, heterocyclic radical,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N, N-two replaces alkylamino, the N-alkenyl amino, N, N-two alkenyl aminos, N-substituted alkenyl base amino, N, N-two substituted alkenyl base amino, the N-naphthene amino, N, N-two naphthene aminos, N-substituted ring alkylamino, N, N-two substituted ring alkylaminos, the N-virtue is amino, N, the N-diarylamino, N-is assorted, and virtue is amino, N, N-two assorted virtues are amino, N-heterocyclic radical amino, N, amino and the mixing N of N-two heterocyclic radicals, N-amino, described mixing N, N-amino comprises one first substituting group and one on described amino disubstituted, described substituting group is selected from alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical, prerequisite are that described first and second substituting groups are inequality;

Prerequisite is to have structure (i) as A, and B is when having structure (i), and C does not have structure (i) or (ii);

Other prerequisite is,

A. work as A and have structure (i), wherein R ¹Be phenyl, Z is-CH ₂OC (O)-, R ₂Be methyl, and p is 0, B has structure (iii), and wherein W is-NH-, and X is-CH ₂-, and R ⁴During for benzyl, C is not-C (O) OCH ₃

B. work as A and have structure (i), wherein R ¹Be 3, the 5-difluorophenyl, Z is-CH ₂C (O)-, R ₂Be methyl, p is 0, and B has structure (ii), and wherein W is＞NC (O) OC (CH ₃) ₃, X is-CH ₂-, R ⁴Be phenyl, then C is not-C (O) OCH ₃And

C. work as A and have structure (ii), wherein R ¹Be 3, the 5-difluorophenyl, T ' is for connecting R ¹With-CX ' X "-key, X ' and X " be hydrogen, W is a sulphur, X is a methylene radical, R ⁴Be methyl, and B is when connecting the covalent linkage of A and C, then C is not-C (O) OCH ₃

In a preferred embodiment, formula I compound also characterizes by having with Formula Il:

R wherein ¹, R ², R ⁵, R ⁶, definition in A, Z, m and p such as the claim 1.

In with following formula II, when m was 1, Z was preferably-CX ' X " C (O)-, X wherein " and be preferably hydrogen, X ' is preferably hydrogen or fluorine, or X ' and X " form an oxo base.

In with following formula II, preferred R ¹Unsubstituting aromatic yl comprises for example phenyl, 1-naphthyl and 2-naphthyl etc.

Preferred R among the formula II ¹Substituted aryl comprises for example monosubstituted phenyl (preferably 3 or 5 substituting groups); Di-substituted-phenyl (preferably 3,5 substituting groups) and tri-substituted phenyl (preferably 3,4,5 substituting groups) etc.Preferably, described substituted-phenyl does not comprise more than 3 substituting groups.

The preferred R that replaces among the formula II ¹The example of phenyl comprises for example 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

Preferred R among the formula II ¹Alkaryl comprises for example benzyl, 2-phenylethyl and 3-phenyl n-propyl etc.

Preferred R among the formula II ¹Alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group for example comprise sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl etc.

Preferred R among the formula II ¹Heteroaryl and substituted heteroaryl comprise for example pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base etc.

Preferably, R in formula II ²Be selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical.Particularly preferred R ²Substituting group for example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃Deng.As described below, R ²And R ⁵And R ⁶Be preferably the amino acid whose side chain of L-.

Preferred R among the formula II ⁵And/or R ⁶Substituting group be independently selected from as hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

In formula II, preferred

Group is also by following structural characterization:

Y wherein " for be selected from oxygen, sulphur and＞NR ⁸Heteroatoms, R wherein ⁸As above-mentioned definition, and A ' is with-Y "-C=N-forms heterocyclic radical; this heterocyclic radical can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl; cycloalkenyl group; heterocyclic radical; aryl and heteroaryl; each in this ring structure again can be randomly with being selected from following 1-4 substituting group replacement: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N-alkyl N-replaces alkylamino, N, N-two replaces alkylamino, aryl, heteroaryl, heterocyclic radical,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl.

Preferred heterocycle structure comprises for example 3-methyl isophthalic acid, 2, and 4-oxadiazole-5-base, thiazoline-2-base, 3-phenyl-1,2,4-oxadiazole-5-base and 3-(to methoxyl group-benzyl)-1,2,4-oxadiazole-5-base etc.

Preferred formula II compound comprises:

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino] ethyl-3-ethyl-1,2, the 4-oxadiazole

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-2-styroyl]-the 3-methyl isophthalic acid, 2, the 4-oxadiazole

2-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-2-thiazoline

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-3-methyl isophthalic acid, 2, the 4-oxadiazole

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-3-phenyl-1,2, the 4-oxadiazole

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-3-(4-anisole ylmethyl)-1,2, the 4-oxadiazole.

In another embodiment preferred, described formula I compound is also characterized by Formula Il I and IV:

R wherein ¹, R ², R ⁴, R ⁶, W, X, Y, Z, m and p such as above-mentioned definition.

In above formula III and formula IV, when m was 1, Z was preferably-CX ' X " C (O)-, X wherein " and be preferably hydrogen, X ' is preferably hydrogen or fluorine, and wherein X ' and X " form an oxo base.

In above formula III and formula IV, preferred R ¹Unsubstituting aromatic yl comprises for example phenyl, 1-naphthyl and 2-naphthyl etc.

Preferred R among formula III and the formula IV ¹Substituted aryl comprises for example monosubstituted phenyl (being preferably 3 or 5 substituting groups); Di-substituted-phenyl (being preferably 3,5 substituting groups); And tri-substituted phenyl (being preferably 3,4,5 substituting groups).Preferably, described substituted-phenyl does not comprise the substituting group more than 3.

The preferred R that replaces among formula III and the formula IV ¹The phenyl example comprises for example 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

Preferred R among formula III and the formula IV ¹Alkaryl comprises for example benzyl, 2-phenylethyl and 3-phenyl n-propyl etc.

Preferred R among formula III and the formula IV ¹Alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group for example comprise: sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl etc.

Preferred R among formula III and the formula IV ¹Heteroaryl and substituted heteroaryl for example comprise: pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base etc.

Preferably, in formula III and formula IV, R ²Be selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical.Particularly preferred R ²Substituting group for example comprises: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃Deng.As described below, R ²(and R ⁶) be preferably the amino acid whose side chain of L-.

Preferred R among formula III and the formula IV ⁶Substituting group for example comprises: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

Among formula III or the formula IV preferred Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ", wherein R ' and R " as above-mentioned definition.Preferred alkoxyl group and substituted alkoxy comprise: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy etc.Preferably-and NR ' R " group for example comprises: amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl (azetidino), N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (right-aminomethyl phenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂,-NHCH ₂-(tetrahydrofuran (THF)-2-yl) etc.

Another preferred Y group is such as-CH ₂CH ₂CH (CH ₃) ₂Alkyl etc.

For example comprise 4 by the preferred heterocycle structure of W and X definition, 5-thiazoline, 3,4-dihydro-1, the different diazole of 3-, 3, the 4-dihydro-different diazole of 3-N-tert.-butoxy-3-and 4,5-dihydro-oxazole etc.

Preferred formula III and formula IV compound comprise:

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-ethoxycarbonyl-2-thiazoline

1-tert-butyl ester base-2-[1-(N-carbonyl benzyloxy) aminoethyl]-4-methoxycarbonyl-4-phenyl methyl-2-tetrahydroglyoxaline

1-tert-butyl ester base-2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-methoxycarbonyl-4-phenyl methyl-2-tetrahydroglyoxaline

2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-methoxycarbonyl-4-phenyl methyl-2-tetrahydroglyoxaline

2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-4-ethoxycarbonyl-2-thiazoline

1-tert-butyl ester base-2-[1-(N-carbonyl benzyloxy) amino-ethyl]-4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline

2-[(S)-1-(3,5-dichlorobenzene amido) ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-5 (R, S)-ethoxycarbonyl-2-oxazoline

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-4-methoxycarbonyl-2-thiazoline

[1-(N-carbonyl benzyloxy) aminoethyl]-4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline.

In another embodiment preferred, described formula I compound is also characterized by following formula V and VI:

R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W, X and Y such as above-mentioned definition.

In with following formula V and formula VI, when m was 1, Z was preferably-CX ' X " C (O)-, X wherein " and be preferably hydrogen, X ' is preferably hydrogen or fluorine, or X ' and X " form an oxo base.

In with following formula V and formula VI, preferred R ¹Unsubstituting aromatic yl comprises for example phenyl, 1-naphthyl and 2-naphthyl etc.

Preferred R among formula V and the formula VI ¹Substituted aryl comprises for example monosubstituted phenyl (being preferably 3 or 5 substituting groups); Di-substituted-phenyl (being preferably 3,5 substituting groups); And tri-substituted phenyl (being preferably 3,4,5 substituting groups).Preferably, described substituted-phenyl does not comprise the substituting group more than 3.

The preferred R that replaces among formula IV and the formula VI ¹The example of phenyl for example comprises: the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

Preferred R among formula IV and the formula VI ¹Alkaryl comprises for example benzyl, 2-phenylethyl and 3-phenyl n-propyl etc.

Preferred R among formula V and the formula VI ¹Alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group for example comprise: sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl etc.

Preferred R among formula III and the formula IV ⁴Substituting group comprises for example hydrogen, methyl, phenyl and benzyl etc.

Preferred R among formula V and the formula VI ⁶Substituting group for example comprises: hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

Among formula V or the formula VI preferred Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ", wherein R ' and R " as above-mentioned definition.Preferred alkoxyl group and substituted alkoxy comprise: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy etc.Preferably-and NR ' R " group for example comprises amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl, N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (p-methylphenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂-φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂With-NHCH ₂-(tetrahydrofuran (THF)-2-yl) etc.

Another preferred Y group is such as-CH ₂CH ₂CH (CH ₃) ₂Alkyl etc.

Preferred heterocycle structure by W and X definition comprises for example 4-methylthiazol quinoline-4-base.

Preferred formula V and VI compound comprise:

(4R)-and 4-[N-(1S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-(3,5-difluorophenyl methyl)-4-methyl-2-thiazoline

4-[N-(S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-(3,5-difluorophenyl methyl)-2-thiazoline

4-[N-(S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-(3,5-difluorophenyl methyl)-4-methyl-2-tetrahydroglyoxaline.

Another preferred compound of the present invention comprises lactan and the related compound of formula VII and VIII: R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W and X such as above-mentioned definition;

W ' and-C (H) _sC (=U)-together form cycloalkyl, cycloalkenyl group, heterocyclic radical, substituted cycloalkyl or substituted cycloalkenyl, wherein said cycloalkyl, cycloalkenyl group, heterocyclic radical, each of substituted cycloalkyl or substituted cycloalkenyl can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, in this ring structure each can randomly replace with being selected from following 1-4 substituting group again: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, aryl, heteroaryl, heterocyclic radical, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N-alkyl N-replaces alkylamino, N, N-two replaces alkylamino,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl;

U be selected from oxo (=O), the sulfo-oxo (=S), hydroxyl (H ,-OH), thiol (H ,-SH) and hydrogen (H, H);

S is 0 or 1 integer; And

T is 0 or 1 integer.

In with following formula VII and formula VIII, X " be preferably hydrogen, X ' is preferably hydrogen or fluorine, or X ' and X " form an oxo base, and T ' is preferably connection R ¹With-CX ' X "-covalent linkage.

In with following formula VII and formula VIII, preferred R ¹Unsubstituting aromatic yl comprises for example phenyl, 1-naphthyl and 2-naphthyl etc.

Preferred R among formula VII and the formula VIII ¹Substituted aryl comprises for example monosubstituted phenyl (preferably 3 or 5 substituting groups); Disubstituted phenyl (preferably 3,5 substituting groups) and tri-substituted phenyl (preferably 3,4,5 substituting groups).Preferably, described substituted-phenyl does not comprise more than 3 substituting groups.

The preferred R that replaces among formula VII and the formula VIII ¹The example of phenyl comprises the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

Preferred R among formula VII and the formula VIII ¹Alkaryl comprises for example benzyl, 2-phenylethyl and 3-phenyl n-propyl etc.

Preferred R among formula VII and the formula VIII ¹Alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group for example comprise sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl etc.

Preferred R among formula VII and the formula VIII ¹Heteroaryl and substituted heteroaryl comprise for example pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base etc.

Preferred R among formula VII and the formula VIII ⁴Substituting group comprises for example hydrogen, methyl, phenyl, benzyl etc.

Preferred R among formula VII and the formula VIII ⁶Substituting group for example comprise hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

By W ' and-C (H) _sC (=U)-definition preferred cyclic group comprise cycloalkyl, lactone, lactan, benzo-aza ketone (benzazepinone), dibenzo azatropylidene ketone and benzodiazepine group.In a preferred embodiment, by W ' and-C (H) _sC (=U)-cyclic group of definition forms the cycloalkyl of following formula: T wherein " be selected from alkylidene group and substituted alkylene.

Preferred cycloalkyl is expressed from the next:

Wherein each V is independently selected from hydroxyl, acyl group, acyloxy, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano group, halo, nitro, heteroaryl, thio alkoxy, replacement thio alkoxy, trihalomethyl group etc.; R ^aBe selected from alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, amino, carboxyl, carboxyalkyl, cyano group, halo etc.; T is the integer of 0-4; And w is the integer of 0-3.

T is preferably the integer of 0-2, more preferably 0 or 1 integer.

In another embodiment preferred, by W ' and-C (H) _sC (=U)-definition cyclic group be the ring of following formula:

Or

Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-,-S-and＞NR ¹²Substituting group, each R ¹²Be independently selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocyclic radical, each R ¹³Be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group independently, preceding topic be when Z for-O-or-during S-, described alkylene group and replace any unsaturated in the alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

Particularly preferred alcohol or thiol substituting group comprise

T is preferably the integer of 0-2, more preferably 0 or 1 integer.

In another preferred embodiment, by W ' and-C (H) _sC (=U)-definition cyclic group be the ring of following formula: Or

Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-, o and＞NR ¹²Substituting group, each R ¹²Be independently selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocyclic radical, each R ¹³Be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group independently, preceding topic be when Z for-O-or-during S-, described alkylene group and replace any unsaturated in the alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

Particularly preferred cyclic ketones and thioketones base comprise

T is preferably the integer of 0-2, more preferably 0 or 1 integer.

In another preferred embodiment, by W ' and-C (H) _sC (=U)-cyclic group of definition forms the ring of following formula:

Or Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-,-S-and＞NR ¹²Substituting group, each R ¹²Be independently selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocyclic radical, each R ¹³Be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group independently, prerequisite be when Z for-O-or-during S-, described alkylene group and replace any unsaturated in the alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

Particularly preferred lactone and thiolactone group comprise:

Wherein each V is independently selected from hydroxyl, acyl group, acyloxy, alkyl, substituted alkyl, alcoxyl

Base, substituted alkoxy, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano group, halo, nitro, heteroaryl, thio alkoxy, replacement thio alkoxy, trihalomethyl group etc.; R ^aBe selected from alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, amino, carboxyl, carboxyalkyl, cyano group, halo etc.; T is the integer of 0-4; And w is the integer of 0-3.

T is preferably the integer of 0-2, more preferably 0 or 1 integer.

In another preferred embodiment, by W ' and-C (H) _sC (=U)-cyclic group of definition forms the lactam nucleus of following formula:

Or the thio lactam ring of following formula: Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-,-S-and＞NR ¹²Substituting group, each R ¹²Be independently selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocyclic radical, each R ¹³Be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group independently, preceding topic be when Z for-O-or-during S-, described alkylene group and replace any unsaturated in the alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

Particularly preferred lactan and thio lactam group comprise: Wherein A-B be selected from alkylidene group, alkylene group, substituted alkylene, replacement alkylene group and-N=CH-; Q ' is oxygen or sulphur; Each V independently is selected from hydroxyl, acyl group, acyloxy, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano group, halo, nitro, heteroaryl, thio alkoxy, replacement thio alkoxy, trihalomethyl group etc.; R ^aBe selected from alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, amino, carboxyl, carboxyalkyl, cyano group, halo etc.; R ^bBe selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, acyl group, aryl, heteroaryl, heterocyclic radical etc.; R ^cBe selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, aryl, heteroaryl, heterocyclic radical, cycloalkyl and substituted cycloalkyl etc.; T is the integer of 0-4; T ' is the integer of 0-3; W is the integer of 0-3.

Preferred t is the integer of 0-2; More preferably t is 0 or 1.

In another preferred embodiment, by W ' and-C (H) _sC (=U)-cyclic group of definition forms the ring of following formula: Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-,-S-and＞NR ¹²Substituting group, each R ¹²Independently be selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocycle, each R ¹³Independent be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group, prerequisite for as Z be-O-or-during S-, any unsaturated in so described alkylene group and the replacement alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

Another embodiment preferred relate to by W and-C (H) _sC (=U)-cyclic group of following formula of definition: Wherein s is 0 or 1, T " be selected from alkylidene group, substituted alkylene, alkylene group, replacement alkylene group ,-(R ¹³Z) _qR ¹³-and-ZR ¹³-, wherein Z for be selected from-O-,-S-and＞NR ¹²Substituting group, each R ¹²Independently be selected from alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, substituted alkyl, substituted alkenyl base, replace alkynyl group, aryl, heteroaryl and heterocycle, each R ¹³Independent be alkylidene group, substituted alkylene, alkylene group and replacement alkylene group, prerequisite for as Z be-O-or-during S-, any unsaturated in so described alkylene group and the replacement alkylene group do not comprise described-O-or-participation of S-, and q is the integer of 1-3.

The present invention's preferred compound again comprises lactan and the related compound of formula IX and formula X: R wherein ¹, R ², R ⁴, Z, U, W, W ', X, m and s such as above-mentioned definition.

Preferred R ¹, R ², R ⁴, Z, W and W ' also as above-mentioned definition.

Aspect one of its method, the present invention relates to suppress in the cell beta amyloid peptide and discharge and/or its synthetic method, this method comprises and gives this cell to suppress cell and discharge and/or to synthesize following formula I, VII and a kind of compound of VIII or the mixture of compound of beta amyloid peptide significant quantity.

Because produce relevant in the body of beta amyloid peptide with the pathogeny of AD ^8,9, so the compound of formula I, VII and VIII also can be used in combination with a kind of medicinal compositions, with preventative and/or therapeutic prevent and/or treat AD.Therefore, in its method on the other hand, the present invention relates to the Preventive Method of prevention AD outbreak in the patient who develops into the AD risk is arranged, this method comprises and gives described patient a kind of medicinal compositions, and described medicinal compositions comprises pharmaceutically a kind of above-mentioned formula I, VII and the compound of VIII or the mixture of compound of inert carrier and significant quantity.

Its method another aspect, the present invention relates to treat the patient who suffers from AD so that suppress the therapeutic method that this disease further worsens, this method comprises and gives described patient a kind of medicinal compositions, and described medicinal compositions comprises pharmaceutically a kind of above-mentioned formula I, VII and the compound of VIII or the mixture of compound of inert carrier and significant quantity.

The present invention also provides novel pharmaceutical compositions, and described novel pharmaceutical compositions comprises the compound of a kind of pharmaceutically inert carrier and a kind of above-mentioned formula I, VII or VIII.

Moreover, the invention provides the compound of new I, VII or VIII.

Further preferred formula I compound is shown among the following table I-IV, and these structures of preferred subgroup are described:

Table I

???????????R ^1’	????R ²	????R ⁴	??????Y	???????W	??????X
???????????R ^1’	????R ²	????R ⁴	??????Y	???????W	??????X	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	?????H	??-OCH ₂CH ₃	???????S	????-CH ₂-
?????-φ-CH ₂-OC(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	?????H	??-OCH ₂CH ₃	???????S	????-CH ₂-
?????-φ-CH ₂-OC(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-
3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	??????NH	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-
3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	???-CH ₂φ	????-OCH ₃	??????NH	????-CH ₂-	??????φ-CH ₂OC(O)-	???-CH ₃	????-φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-
3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	????-φ	????-OCH ₃	??????NH	????-CH ₂-	??????φ-CH ₂OC(O)-	???-CH ₃	????-φ	????-OCH ₃	????-N-t-Boc	????-CH ₂-
3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	????-φ	????-OCH ₃	??????NH	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	????H	????-OCH ₃	???????O	????-CH ₂-
3,5-two-Cl-φ-CH ₂C(O)-	???-CH ₃	????H	????-OCH ₃	???????O	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	???-CH ₃	????H	????-OCH ₃	???????O	????-CH ₂-
3,5-two-Cl-φ-CH ₂C(O)-	???-CH ₃	????H	????-OCH ₃	???????O	????-CH ₂-	3,5-two-F-φ-CH ₂C(O)-	????-φ	????H	????-OCH ₃	???????S	????-CH ₂-

Table II

???????????R ^1’	????R ²	???R ⁴	??????Y	????W	?????X
???????????R ^1’	????R ²	???R ⁴	??????Y	????W	?????X	3,5-two fluoro-φ-CH ₂C(O)-	???-CH ₃	????H	??-OCH ₂CH ₃	????O	???-CH ₂-
3,5-two fluoro-φ-CH ₂C(O)-	???-CH ₃	??-CH ₂φ	????-OCH ₃	????NH	???-CH ₂-	3,5-two fluoro-φ-CH ₂C(O)-	???-CH ₃	????H	??-OCH ₂CH ₃	????O	???-CH ₂-
3,5-two fluoro-φ-CH ₂C(O)-	???-CH ₃	??-CH ₂φ	????-OCH ₃	????NH	???-CH ₂-	3,5-two fluoro-φ-CH ₂C(O)-	???-CH ₃	????H	????-OCH ₃	????NH	???-CH ₂-

Table III

??????????R ^1’	???R ²	????m	?????R ⁶	?????????????????V
??????????R ^1’	???R ²	????m	?????R ⁶	?????????????????V	3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	????-CH ₃	3-ethyl-1,2,4-oxadiazole-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	???-CH ₂φ	The 3-methyl isophthalic acid, 2,4-oxadiazole-5-base	3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	????-CH ₃	3-ethyl-1,2,4-oxadiazole-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	???-CH ₂φ	The 3-methyl isophthalic acid, 2,4-oxadiazole-5-base	3,5-two-F-φ-CH ₂C(O)-	???--	????0	????-CH ₃	1-(methyl hexanoyl-2-yl)-tetrazolium-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	Thiazoline-2-base	3,5-two-F-φ-CH ₂C(O)-	???--	????0	????-CH ₃	1-(methyl hexanoyl-2-yl)-tetrazolium-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	Thiazoline-2-base	3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	The 3-methyl isophthalic acid, 2,4-oxadiazole-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	3-phenyl-1,2,4-oxadiazole-5-base	3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	The 3-methyl isophthalic acid, 2,4-oxadiazole-5-base
3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	3-phenyl-1,2,4-oxadiazole-5-base	3,5-two-F-φ-CH ₂C(O)-	??-CH ₃	????1	?????-φ	3-(to methoxyl group-benzyl)-1,2,4-oxadiazole-5-base

Table IV

?????????R ^1’	?????????????T	????n	????R ²	??????Y
?????????R ^1’	?????????????T	????n	????R ²	??????Y	3,5-two-F-φ-CH ₂-	????2-R ¹-thiazoline-4-base	????1	????-φ	????-OCH ₃
3,5-two-F-φ-CH ₂-	????2-R ¹-4-methyl-thiazoline-4-base	????1	????-φ	????-OCH ₃	3,5-two-F-φ-CH ₂-	????2-R ¹-thiazoline-4-base	????1	????-φ	????-OCH ₃
3,5-two-F-φ-CH ₂-	????2-R ¹-4-methyl-thiazoline-4-base	????1	????-φ	????-OCH ₃	3,5-two-F-φ-CH ₂-	????2-R ¹-4-methyl-tetrahydroglyoxaline-4-base	????1	????-φ	????-OCH ₃

Detailed Description Of The Invention

As mentioned above, the present invention relates to suppress compound that beta amyloid peptide discharges and/or it synthesizes and therefore has practicality in the treatment Alzheimer.Yet, before describing the present invention in detail, at first define following term.Definition

Term " beta amyloid peptide " is meant that molecular weight is approximately 39-43 the amino acid whose peptide of 4.2kD, this peptide and Glenner etc. ¹The albumen form of describing is homology roughly, comprises the sudden change and the posttranslational modification of normal beta amyloid peptide.At all events plant form, described beta amyloid peptide is about 39-43 amino acid whose fragment of big transmembrane glycoprotein, is called amyloid-beta precursor protein (APP).Its 43 amino acid whose sequences are: 1Asp Ala Glu Phe Arg His Asp Ser Gly Tyr11Glu Val His His Gln Lys Leu Val Phe Phe21Ala Glu Asp Val Gly Ser Asn Lys Gly Ala31Ile Ile Gly Leu Met Val Gly Gly Val Val41Ile Ala Thr (SEQ ID NO:1) or for homologous sequence basic with it.

" alkyl " is meant the univalent alkyl that preferably has 1-10 carbon atom, more preferably has 1-6 carbon atom.The example of this term has such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-hexyl etc.

" substituted alkyl " is meant a preferred 1-10 carbon atom; have 1-3 and be selected from following substituent alkyl: alkoxyl group; substituted alkoxy; acyl group; amido; amino; aminoacyl; aminocarboxylic acid ester; cyano group; cycloalkyl; halogen; hydroxyl; carboxyl; carboxyalkyl; the oxygen acyl group; the oxygen amido; thiol; thio alkoxy; replace thio alkoxy; aryl; heteroaryl; heterocyclic radical; aryloxy; thio-aryloxy; heteroaryloxy; the sulfo-heteroaryloxy; nitro and one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical replaces amine.

" alkylidene group " is meant the divalent alkyl that preferably has 1-10 carbon atom, more preferably has 1-6 carbon atom.The example of this term has such as methylene radical (CH ₂-), ethylidene (CH ₂CH ₂-), the propylidene isomer (for example-CH ₂CH ₂CH ₂-and-CH (CH ₃) CH ₂-) etc.

" alkaryl " be meant preferably in alkylene moiety, have 1-10 carbon atom, in aryl moiety, have 6-10 carbon atom-alkylidene group-aryl.The example of this class alkaryl is benzyl, styroyl etc.

" alkoxyl group " is meant " alkyl-O-" group.Preferred alkoxyl group comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, positive hexyloxy, 1,2-dimethyl butoxy etc.

" substituted alkoxy " is meant " substituted alkyl-O-" group, and wherein substituted alkyl as defined above.

" alkenyl " is meant preferably have 2-10 carbon atom, more preferably have 2-6 carbon atom and have at least 1, the alkenyl in preferred 1-2 the unsaturated site of alkene.Preferred alkenyl comprises vinyl (CH=CH ₂), positive propenyl (CH ₂CH=CH ₂), pseudoallyl (C (CH ₃)=CH ₂), but-2-ene base (CH ₃CH=CHCH ₃) etc.

" substituted alkenyl base " is meant that having 1-3 is selected from following substituent alkenyl as defined above: alkoxyl group; substituted alkoxy; acyl group; amido; amino; aminoacyl; aminocarboxylic acid ester; cyano group; halogen; hydroxyl; carboxyl; carboxyalkyl; cycloalkyl; the oxygen acyl group; the oxygen amido; thiol; thio alkoxy; replace thio alkoxy; aryl; heteroaryl; heterocyclic radical; nitro and one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical replaces amine.

" alkylene group " is meant the divalence alkylene group that preferably has 2-8 carbon atom, more preferably has 2-6 carbon atom.The example of this term be vinylidene (CH=CH-), the propenylidene isomer (for example-CH ₂CH=CH-and-C (CH ₃)=CH-) etc.

" replacement alkylene group " is meant preferably have 2-8 carbon atom; have 1-3 and be selected from following substituent alkylene group: alkoxyl group; substituted alkoxy; acyl group; amido; acyloxy; amino; aminoacyl; the ammonia acyloxy; cyano group; halogen; hydroxyl; carboxyl; carboxyalkyl; thiol; thio alkoxy; replace thio alkoxy; aryl; heteroaryl; heterocyclic radical; nitro and one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical replaces amine.Therefore, this class substituted alkylene comprises such substituted alkylene, and 2 substituting groups on the wherein said alkylidene group are in conjunction with forming one or more and described alkylidene group bonded cycloalkyl, aryl, heterocyclic radical or heteroaryl.

" alkynyl group " is meant preferably have 2-10 carbon atom, more preferably have 2-6 carbon atom and have at least 1, the alkynyl group in preferred 1-2 the unsaturated site of alkynes.Preferred alkynyl group comprises ethynyl (C ≡ CH), propargyl (CH ₂C ≡ CH) etc.

" replacement alkynyl group " is meant that having 1-3 is selected from following substituent alkynyl group as defined above: alkoxyl group; substituted alkoxy; acyl group; amido; amino; aminoacyl; aminocarboxylic acid ester; cyano group; halogen; hydroxyl; carboxyl; carboxyalkyl; cycloalkyl; the oxygen acyl group; the oxygen amido; thiol; thio alkoxy; replace thio alkoxy; aryl; heteroaryl; heterocyclic radical; nitro and one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical replaces amine.

" acyl group " be meant alkyl-C (O)-, substituted alkyl-C (O)-, cycloalkyl-C (O)-, aryl-C (O)-, heteroaryl-C (O)-and heterocycle-C (O)-, wherein alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocycle as above define.

" amido " is meant-C (O) NRR group that each R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic radical independently here, and wherein each alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical as above define.

" aminoacyl " is meant group-NRC (O) R, and each R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical independently here, and wherein each alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical as above define.

" oxygen acyl group " be meant group-OC (O)-alkyl ,-OC (O)-aryl ,-C (O) O-heteroaryl and-C (O) O-heterocycle, alkyl, aryl, heteroaryl and heterocyclic radical as above define here.

" oxygen amido " be meant group-OC (O) NR-alkyl ,-OC (O) NR-substituted alkyl ,-OC (O) NR-aryl ,-OC (O) NR-heteroaryl-and-OC (O) NR-heterocyclic radical, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical, and wherein each in alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and the heterocyclic radical as above defines.

" aminocarboxylic acid ester " be meant group-NRC (O) O-alkyl ,-NRC (O) O-substituted alkyl ,-NRC (O) O-aryl ,-NRC (O) O-heteroaryl and-NRC (O) O-heterocyclic radical, wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical, and wherein each in alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and the heterocyclic radical as above defines.

" aryl " is meant the unsaturated aromatic carbocyclic group of 6-14 carbon atom of have monocycle (for example phenyl) or a plurality of condensed ring (for example naphthyl or anthryl).Preferred aryl groups comprises phenyl, naphthyl etc.

Unless definition limits in addition to aryl substituent, otherwise can randomly being selected from following substituting group with 1-3, this class aryl replaces: hydroxyl; acyl group; alkyl; alkoxyl group; alkenyl; alkynyl group; substituted alkyl; substituted alkoxy; the substituted alkenyl base; replace alkynyl group; amino; aminoacyl; aminocarboxylic acid ester; alkaryl; aryl; aryloxy; carboxyl; carboxyalkyl; amido; cyano group; halo; nitro; heteroaryl; heterocyclic radical; the oxygen acyl group; the oxygen amido; thio alkoxy; replace thio alkoxy; trihalomethyl group; one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical etc. replaces amine.Preferred substituted comprises alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group and thio alkoxy.

" aryloxy " is meant group aryl-O-, and wherein said aryl as above defines, and comprises the aryl that also can choose replacement as defined above wantonly.

" carboxyalkyl " be meant group-C (O) O-alkyl and-C (O) O-substituted alkyl, alkyl and substituted alkyl as above define here.

" cycloalkyl " is meant the monocycle with 3-8 carbon atom or the cycloalkyl of a plurality of condensed ring, and described monocycle or condensed ring can be randomly with 1-3 alkyl replacements.This type of cycloalkyl comprises for example single ring architecture, such as cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.; Or a plurality of ring structures such as adamantyl etc.

" substituted cycloalkyl " is meant that having 1-5 individual (preferably having 1-3) is selected from following substituent cycloalkyl: hydroxyl, acyl group, acyloxy, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano group, halo, nitro, heteroaryl, thio alkoxy, replacement thio alkoxy, trihalomethyl group etc.

" cycloalkenyl group " is meant the cycloalkenyl group of 4-8 carbon atom with monocycle and at least one inner unsaturated point, and described cycloalkenyl group can randomly replace with 1-3 alkyl.The example of suitable cycloalkenyl group comprises and for example encircles but-2-ene base, ring penta-3-thiazolinyl, ring suffering-3-thiazolinyl etc.

" substituted cycloalkenyl " is meant that having 1-5 is selected from following substituent cycloalkenyl group: hydroxyl, acyl group, acyloxy, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxyalkyl, cyano group, halo, nitro, heteroaryl, thio alkoxy, replacement thio alkoxy, trihalomethyl group etc.

" halo " or " halogen " is meant fluorine, chlorine, bromine and iodine, preferably chlorine or bromine.

" heteroaryl " is meant to have to have 1-4 heteroatomic monovalence aromatic carbocyclic group that is selected from oxygen, nitrogen and sulphur in 2-10 carbon atom and this ring.

Unless to heteroaryl substituting group definition restriction in addition, otherwise this class heteroaryl can randomly replace with being selected from following 1-3 substituting group: hydroxyl; acyl group; alkyl; alkoxyl group; alkenyl; alkynyl group; substituted alkyl; substituted alkoxy; the substituted alkenyl base; replace alkynyl group; amino; aminoacyl; aminocarboxylic acid ester; alkaryl; aryl; aryloxy; carboxyl; carboxyalkyl; aminoacyl; cyano group; halo; nitro; heteroaryl; heterocyclic radical; the oxygen acyl group; the oxygen amido; thio alkoxy; replace thio alkoxy; trihalomethyl group; one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical etc. replaces amine.Preferred substituted comprises alkyl, alkoxyl group, halo, cyano group, nitro, trihalomethyl group and thio alkoxy.

This type of heteroaryl can have monocycle (as pyridyl or furyl) or a plurality of condensed ring (as indolizine base or benzothienyl).Preferred heteroaryl comprises pyridyl, pyrryl and furyl.

" heterocyclic radical " or " heterocyclic " is meant to have monocycle or a plurality of condensed ring, have in 1-8 carbon atom and the ring and have the saturated or unsaturated group of heteroatomic unit price that 1-4 is selected from nitrogen, sulphur or oxygen.

Unless, replace otherwise this class heterocyclic radical can randomly be selected from following substituting group with 1-3: hydroxyl to heterocyclic substituent definition restriction in addition; acyl group; alkyl; alkoxyl group; alkenyl; alkynyl group; substituted alkyl; substituted alkoxy; the substituted alkenyl base; replace alkynyl group; amino; aminoacyl; aminocarboxylic acid ester; alkaryl; aryl; aryloxy; carboxyl; carboxyalkyl; aminoacyl; cyano group; halo; nitro; heteroaryl; heterocyclic radical; the oxygen acyl group; the oxygen amido; thio alkoxy; replace thio alkoxy; trihalomethyl group; one-and two-alkylamino; one-and two-(substituted alkyl) amino; one-and two-Fang amino; one-and two-assorted virtue is amino; one-and two-heterocyclic amino group and have the alkyl of being selected from; substituted alkyl; aryl; asymmetric two of the different substituents of heteroaryl and heterocyclic radical etc. replaces amine.This class heterocyclic radical can have monocycle or a plurality of condensed ring.Preferred heterocycle comprises morpholino, piperidyl etc.

The example of heterocyclic radical and heteroaryl includes but not limited to the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, 2, the 3-naphthyridine, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, phenanthroline, isothiazole, azophenlyene isoxazole phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1,2,3, the 4-tetrahydroisoquinoline, 4,5,6,7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, piperidyl, tetramethyleneimine, tetrahydrofuran base etc.

" oxygen acyl group " be meant group-OC (O)-alkyl ,-OC (O)-aryl ,-C (O) O-heteroaryl and-C (O) O-heterocyclic radical, wherein alkyl, aryl, heteroaryl and heterocyclic radical as above define.

" oxygen amido " be meant group-OC (O) NH-alkyl ,-OC (O) NH-substituted alkyl ,-OC (O) NH-aryl ,-OC (O) NH-heteroaryl and-OC (O) NH-heterocyclic radical, wherein alkyl, aryl, heteroaryl and heterocyclic radical as above define.

" thiol " is meant group-SH.

" thio alkoxy " is meant group-S-alkyl.

" replacement thio alkoxy " is meant group-S-substituted alkyl.

" thio-aryloxy " is meant group aryl-S-, and wherein said aryl as above defines, and comprises as defined above and can choose substituted aryl wantonly.

" sulfo-heteroaryloxy " is meant group heteroaryl-S-, and wherein said heteroaryl as above defines, and comprises as defined above and can choose substituted aryl wantonly.

" pharmacy acceptable salt " is meant the pharmacy acceptable salt of formula I, VII or VIII compound, and described salt comprises sodium, potassium, calcium, magnesium, ammonium, tetra-allkylammonium etc. derived from all organic and inorganic counter ions well known in the art as just example; And when this molecule contained an alkaline functionality, the salt of organic or inorganic acid all can be used as pharmacy acceptable salt such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate, oxalate etc.The preparation of compound

By several different route of synthesis, preparation I compound easily, described route of synthesis is for selecting relatively easily to prepare the particular approach of compound, and raw material can commercially availablely obtain.

By using or revising the synthetic and method of known chemical well known in the art, can prepare with the heterocycle in the following formula I compound.It is synthetic for example to describe various heterocyclic in embodiment proposed below in detail.Use these methods,, can prepare other suitable heterocycle by changing the raw material in these methods.

In some cases, the suitable heterocycle by will having one or more side chain functionalities and other essential component coupling, the A-B-C structure that forms formula I prepares the compound with following formula I.The typical functional groups that is used for this class coupling comprises for example carboxylic acid and amino.Generally under the situation of using or do not use additive such as the N-hydroxy-succinamide known, I-hydroxybenzotriazole etc., can use conventional coupling reagent to promote coupling such as carbodiimide.This reaction is carried out described thinner such as dimethyl formamide, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF) etc. usually in the non-proton polarity thinner of inertia.

By the carboxylic acyloxy amination of the routine shown in the following reaction (1), the easily compound of preparation formula VII and VIII:

R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W, X, W ', U, t and s such as above-mentioned definition.

This reaction is usually carried out with the carboxylic acid 1a of stoichiometric quantity at least or 1b and amine 2.This reaction is undertaken by peptide synthetic method usually, and the synthetic method of using of peptide also can be used for preparation formula VII and VIII compound.For example, under the situation of using or do not use the additive known such as N-hydroxy-succinamide, I-hydroxybenzotriazole etc., can use the coupling reagent known such as carbodiimide to promote coupling.This reaction is for example carried out in dimethyl formamide, methylene dichloride, chloroform, acetonitrile, the tetrahydrofuran (THF) etc. at the non-proton polarity thinner of inertia usually.Perhaps, in reaction (1), can use the carboxylic acid halides of compound 1a or 1b, when used as such, generally in the presence of suitable alkali (acid that produces in the cleaning reaction), carry out.Suitable alkali comprises as triethylamine, diisopropylethylamine, N-methylmorpholine etc.Synthesizing of carboxylic acid raw material

By several different route of synthesis, can prepare carboxylic acid 1a and 1b, described route of synthesis is for selecting relatively easily to prepare the particular approach of compound, and no matter t is 0 or 1, and raw material all can commercially availablely obtain.A method for preparing these compounds (when t is 1) is the hydrolysis of the ester of following formula V and VI compound.It is 0 related compound that similar methods can be used for preparing t.

Utilize the carbodiimide peptide coupling reagent of polymkeric substance its load form, also can prepare m etc. 1, the carboxylic acid 1 that n equals 1 or 2.The EDC (Tetrahedron Letters, 34 (48), 7685 (1993)) 10 of polymkeric substance its load form has for example been described.In addition, also found new carbodiimide coupling reagent PEPC and corresponding polymer its load form thereof, they are very useful when this compounds of preparation.

Be adapted at preparing the polymkeric substance that uses in the coupling reagent of polymkeric substance load or obtain, perhaps the method preparation that can know with the polymer arts technician by commerce.Suitable polymkeric substance must have side chain, have on this side chain can with the part of carbodiimide end group amine reaction.These reactive moieties comprise chlorine, bromine, iodine and methylsulfonyl.Described reactive moieties is preferably the chloro methyl.In addition, the skeleton of polymkeric substance must be an inert to the condition of the coupling reagent use of carbodiimide and final polymkeric substance combination.

The chloro that some methylolated resin can be converted into the coupling reagent that is used to prepare the polymkeric substance load resin that methylates.The example of these hydroxylation resins comprises 4-hydroxymethyl phenyl acetylamino methyl resin (Pam resin) and 4-benzyloxy benzylalcohol resin (Wang resin), can be by Advanced Chemtech of Louisville, the Kentucky U.S. (referring to the products catalogue of AdvancedChemtech 1993-1994, the 115th page) obtains.Any in the whole bag of tricks of knowing by the technician can be converted into the methylol of these resins required chloro methyl.

Because its commercial availability, so preferred resin is the methylated vinylbenzene/divinylbenzene resin of chloro.Shown in title, these resin caproyl chlorides do not need chemical modification before use for methylating.The commercial MerrfieldShi resin that is called of these resins can derive from Aldrich Chemical Company of Milwaukee, the Wisconsin U.S. (referring to the year product catalogue of Aldrich 1994-1995, the 899th page).The method such as the general introduction of following flow process that prepare PEPC and polymkeric substance its load form thereof.

These class methods are more detailed description in U.S. Patent application series the 60/019th, No. 790 (submission on June 14th, 1996), and this application is attached to herein by reference.In brief, at first by making ethyl isocyanate and 1-(3-aminopropyl) tetramethyleneimine prepared in reaction PEPC.Handle the urea that produces with the 4-toluene sulfonyl chloride and obtain PEPC.Under standard conditions, make PEPC and suitable resin reaction prepare the polymkeric substance its load form, obtain required reagent.

The carboxylic acid coupled reaction of carrying out with these reagent in about room temperature to about 45 ℃ of about 3-120 hours.Generally speaking, can separated product by usefulness chloroform washing reaction thing and concentrating under reduced pressure residual organic matter.As discussed above, greatly simplified in conjunction with separated product the reactant of reagent from using polymkeric substance, promptly only need filter reaction mixture, concentrating under reduced pressure filtrate gets final product then.The preparation of cyclic amino compound

The cyclic amino compound 2 that uses in above reaction (1) is generally amino lactan, amino lactone, amino thiolactone and amino compound cycloalkyl, can be represented by following formula:

Wherein U is identical with above-mentioned definition with s, Q preferably from-O-,-S-,＞NR ¹⁶With＞CR ¹⁷R ¹⁸Each R wherein ¹⁶, R ¹⁷And R ¹⁸Independently be selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl base, alkynyl group, replacement alkynyl group, aryl, heteroaryl and heterocyclic radical, prerequisite be if Q for-O-,-S-or＞NR ¹⁶, X is oxo or dihydro so.

By using or improving the chemical synthesis process of describing in detail in the known document, can prepare the amino lactan of following formula, amino lactone and amino thiolactone.As " the synthesizing of lactone and lactan " referring to Ogliaruso and Wolfe, editors such as Patai, J.Wiley﹠amp; Sons, New York, New York, USA, the 1085th page of grade (1993).

Specifically, shown in following reaction (5), by making suitable α, ω-diamino acid esters 12 direct cyclisation, can prepare the amino lactan 13 that replaces of the 3-with 5,6 or 7 annular atomses:

Reaction (5) wherein L is the linking group (being generally alkylidene group) of 2-4 atom, and Pr is suitable blocking group such as tert-butyl ester base, carbonyl benzyloxy etc., R ¹⁹Be alkoxyl group or aryloxy, as methoxyl group, oxyethyl group, right-nitro-phenoxy, N-succinimide oxygen base (succinimidoxy) etc.This reaction can be carried out in solvent such as water, methyl alcohol, ethanol, pyridine etc.This type of reaction to be exemplified as according to Ugi etc. be hexanolactam with the cyclization of Methionin ester described in Tetrahedron 52 (35): the 11657-11664 (1996).Perhaps, this cyclization also can form lactan in the presence of dewatering agent such as aluminum oxide or silicon-dioxide, as Bldade-Font described in the Tetrahedron Lett.21:2443 (1980).

The preparation of the amino lactan of the aminoalkyl groupization on the cyclic lactam,, is illustrated by following reaction (6) described in the 47:104-109 (1982) at J.Org.Chem. by Freidinger etc.:

Reaction (6) is L and R wherein ¹⁶Identical with above-mentioned definition.

In reaction (6),, with encircling closure, obtain amino lactan 16 subsequently as the method for using EDC with 15 pairs 14 reduction aminations of aldehyde.The preparation of 6 membered lactams that carry out with this universal method is described in J.Med.Chem. by Semple etc., among the 39:4531-4536 (1996).

With intramolecular cyclization reaction particularly advantageous when synthesizing less cyclic lactam that halogenide or its suitable thing carry out amide anion, this moment, the stereochemistry at amino lactan center was obtained by standard amino acid storehouse (pool).This method is described in following reaction (7): Reaction (7) is R wherein ¹⁶Identical with above-mentioned definition.

At J.Org.Chem., 47:104-109 provides in (1982) method of reaction (7) by Semple etc. (above) and Freidinger etc., and wherein the dimethyl sulphide leavings group is handled 17 generations of alkyl methyl sulphur by methyl-iodide, obtains lactan 18.Be reflected at Mitsunobu the similar approach of reacting on the ω alcohol referring to Holladay etc. at J.Org.Chem., described in the 56:3900-3905 (1991).

In another approach, reset (as Donaruma etc. at Organic Reactions with the Bechmann that knows, described in the 11:1-156 (1960)), perhaps use the Schmidt that the knows reaction (Wolff as shown in following reaction (8), Organic Reactions, 3:307-336 (1946)), can prepare lactan 20 by cyclic ketones 19:

Wherein L is identical with above-mentioned definition in reaction (8).

The application of these two reactions can obtain various lactan, the dihydro lactan of tool on the α of lactan carbonyl carbon particularly, and these lactan can form preferred lactan group in above-mentioned formula I compound synthetic.In these reactions, the L group can be the alterable height group, comprises as alkylidene group, substituted alkylene and can contain alkylidene group, and prerequisite is that the carbonyl of heteroatoms and compound 19 is not the ortho position.In addition, Beckmann resets and to go for dicyclo ketone, as Krow etc. at J.Org.Chem., described in the 61:5574-5580 (1996).

The preparation of lactone can seemingly be carried out with the Baeyer-Villiger response class that peracid carries out on ketone.Perhaps, can be that carboxylic acid can prepare thiolactone with ω-SH group cyclisation, through P ₂S ₅Oxo group is converted into the sulfo-oxo group, perhaps uses commercially available LawessonShi reagent (Tetrahedron, 35:2433 (1979)) can prepare thio lactam.

The approach of a beta-lactams synthesis of report is by using alkyl azide to carry out improved Schmidt reaction (intermolecular or intramolecularly), carrying out via the alkyl azide functional group that attacks the restriction of ketone under acidic conditions recently.Gracias etc. described the method for intermolecular reaction among the 117:8047-8048 (1995), and Milligan etc. have described the method for intramolecular reaction at J.Am.Chem.Soc. among the 117:10449-10459 (1995) at J.Am.Chem.Soc..An example of intramolecular reaction method reacts in (9) below to be described:

Reaction (9) is R wherein ¹⁰For as alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic radical.

In this reaction, ketone 21 is converted into α-(ω-alkyl) ketone 22, and its cyclisation is formed bicyclic lactam 23.This type of intramolecular reaction can be used to form the bicyclic lactam with 5-7 unit and have the lactam nucleus of 6-13 unit.Non-response location use heteroatoms at these rings is feasible when bicyclic lactam is mixed in preparation.

The approach of another nearest beta-lactams synthesis,, illustrates in the reaction (10) described in the document of 118:9606-9614 (1996) and citation at J.Am.Chem.Soc. below referring to Miller etc.:

R wherein ⁶Identical with Pr with above-mentioned definition, R ¹¹For as halo, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic radical, wherein said aryl, heteroaryl, cycloalkyl and heterocyclic radical are optional to condense with the lactam nucleus structure.

Specifically, in reaction (10), by ruthenium or the catalytic alkene replacement(metathesis)reaction of molybdenum match, can form undersaturated lactan 25 (this material without further modify use) by suitable unsaturated amides (as 24) thus form lactan 26.Yet, unsaturated in 25 makes can use multiple technologies such as hydoboration, Sharpless or Jacobsen epoxidation, Sharpless dihydroxy to turn usefulness, Diels-Alder addition reaction, Dipolar Cycloaddition and chemistry widely into, to obtain various substituting groups on lactam nucleus.And the replacement subsequent transformation of formation can produce other substituting group (as the methylsulfonylization of alcohol and nucleophilic substitution reaction subsequently).Referring to as Advanced Organic Chemistry such as March, Reaction Mechanisms and Structure, the 2nd edition, McGraw-Hill BookCompany, New York, New York, the multiple narration that this type of may react of USA (1977).Saturated amide and acid amides 24 conventions used in this reaction can be obtained by commerce.

The relevant chemistry that the acid amides cyclisation forms lactan referring to Colombo etc. at Tetrahedron Lett., 35 (23): described in the 4031-4034 (1994), and shown in following reaction (11):

Reaction (11) makes proline derivative 27 cyclisation obtain lactan 28 by the tributyl tin basic ringization in this reaction.

Some above-mentioned lactan contains the essential amino of lactan carbonyl α position, and other lactan does not contain.Yet, can introduce essential amino according in several approach of following description any, these approach only are the catalogue of these several up-to-date reference of synthetic method.

For example, in first kind of universal synthesis method, the leavings group of lactan carbonyl α position carries out trinitride or the amine displacement obtains the alpha-amino group lactan.The example of this type of universal synthesis method is for introducing halogen atom, replace with phthalic imidine negatively charged ion or trinitride, the general subsequently hydrogenation by trinitride is translated into amine, as Rogriguez etc. at Tetrahedron, 52:7727-7736 (1996), Parsons etc. are at Biochem.Biophys.Res.Comm., 117:108-113 (1983) and Watthey etc. are at J.Med.Chem., described in the 28:1511-1516 (1985).A concrete method comprises that at TetrahedronLett., 35:3239 (1994) and King etc. are at J.Org.Chem., described in the 58:3384 (1993) as Armstrong etc. as carry out iodate and trinitride replacement(metathesis)reaction on the benzyl lactan.

Another example by this first kind of universal method of the synthetic alpha-amino group lactan of corresponding lactam comprises with azido-displacement trifluoromethanesulfonic acid ester group, as Hu etc. at Tetrahedron Lett., 36 (21): described in the 3659-3662 (1995).

Another example of this first kind of universal method is in the presence of azodicarboxylate and triaryl phosphine, uses open chain reagent, with the suitable thing of pure and mild nitrogen (is-NH ₂Or phthaloyl imino) Mitsunobu reaction, as Wada etc. at Bull.Chem.Soc.Japan, described in the 46:2833-2835 (1973).

Another example of this first kind of universal method is included in 120 ℃, in anhydrous mixture, make alpha-chloro lactan and aniline or alkylamine, obtain 2-(N-aryl or N-alkyl) lactan, as Gaetzi at Chem.Abs., described in the 66:28690m.

In second kind of universal synthesis method, make enolate (enolate) and alkyl nitrite prepared in reaction α oxime, reduction subsequently obtain the alpha-amino group lactam compound.This universal synthesis method be exemplified as Wheeler etc. at Organic Synthesis, accumulate the VI volume, the 840th page described, wherein describes Isopentyl nitrite and reactive ketone and prepare required oxime.J.Med.Chem., describe the reduction of isonitrosomethyl ester (by oxime and methyl-iodide prepared in reaction) at 28 (12): 1886 (1985), by the reduction reaction of Raney-nickel and the catalytic α of palladium catalyst-oximido hexanolactam referring to Brenner etc. at United States Patent (USP) the 2nd, 938, described in 029.

In the third universal synthesis method, can use the direct reaction of enolate and electrophilic nitrogen transfers reagent.The tosyl group trinitride is used in initial reaction, but Evans etc. at J.Am.Chem.Soc., 112:4011-4030 improves it in (1990).Specifically, at Tetrahedron, the azido-that direct introducing can be reduced to amine by hydrogenation is described among the 52:7719-7726 (1996) as Micouin etc.Equally, Evans etc. (above) describe with tri isopropyl benzenesulfonyl base trinitride as with the trinitride transfering reagent of enolate reaction.Butcher etc. are at Tetrahedron Lett., and 37 (37): disclose among the 6685-6688 (1996) in benzodiazepine class series and α-azido-lactan has been reduced to corresponding amino lactan with triphenylphosphine.At last, the diazo transfer of beta-diketon and subsequently diazonium groups be reduced to amino example such as Hu etc. at Tetrahedron Lett., 36 (21): described in the 3659-3662 (1995), he has used Raney-nickel and hydrogen in acetate, and makes solvent with diacetyl oxide.

In the 4th kind of universal method, at first, the N-substituted lactams is converted into 3-alkoxy carbonyl derivative by reacting with dialkyl carbonate and alkali such as sodium hydride.Referring to J.Am.Chem.Soc. as M.L.Reupple etc., pages or leaves such as 93:7021 (1971).The ester that produces is used as the raw material that is converted into the 3-aminoderivative.This conversion can be finished by the reaction of the Curtius shown in following reaction (12):

Wherein Pr is identical with above-mentioned definition in reaction (12), R ¹²Be generally hydrogen, alkyl or aryl.

Curtius reacts by P.A.S.Smith described in the Organic Reactic (1946).According to the reaction conditions of selecting, Pr can be HBoc.For example when R is H, in the presence of the trimethyl carbinol, obtain product with the diphenyl phosphoryl azide processing, wherein Pr is Boc.

The alpha-amino group lactan that is used as ring aminocompound 2 in above-mentioned reaction (1) also comprises ring N-substituted lactams except that comprising ring N-H lactan.The certain methods of preparation ring N-substituted lactams is described in the above.But, say that more generally the method scope for preparing these compounds is directly introduced substituting group to introduce substituting group before lactan forms basically by form the back at lactan.Also can use although imagine secondary alkylogen (productive rate may reduce), preceding a kind of method is generally used alkali and primary alkyl halogen.

Therefore, first kind of universal method of preparation N-substituted lactams can be finished by making described lactan and alkali and alkylogen (or being acrylate in some cases) reaction.This reaction is known, and can use alkali such as sodium amide, sodium hydride, LDA, LiHMDS to carry out in appropriate solvent such as THF, DMF etc., and its prerequisite is compatible for alkali and the solvent selected.Referring to Tetrahedron as K.Orito etc., the J.Med.Chem. of 36:1017-1021 (1980) and J.E.Semple etc., 39:4531-4536 (1996) (use LiHMDS and R-X or with acrylate as electrophilic reagent).

Second kind of universal method used reduction amination on amido functional group, making its cyclisation then is suitable ester or other carbonyl functional group.

The third universal method produces N-and replaces during lactan forms.Particularly the photodissociation carried out of N-aryl compound or thermal rearrangement produce this class N-and replace document citation report by oxa-aziridine (oxaziridine).Referring to Chem.Ber. as Krimm, the J.Chem.Soc.Chem.Comm. of 91:1057 (1958) and Suda etc., 949-950 (1994).Barton etc. also report among the 1764-1767 (1975) that at J.Chem.Soc. using methyl hydroxylamine formation nitrone and their to reset is the N-methyl-derivatives.In addition, Kitagawa etc. are reported in the synthetic middle oxa-aziridine method of using of chirality at J.Am.Chem.Soc. among the 117:5169-5178 (1975).

Akhatar etc. are at J.Org.Chem., and report uses tertiary butyl tetramethyl guanidine and dichloride triphenyl bismuth among the 55:5222-5225 (1990), by the more direct approach of corresponding N H lactan acquisition N-phenyl substituted lactams, shown in following reaction (13):

Reaction (13)

Known several different methods can be used for introducing alpha-amino group on lactan (or lactone) ring, so following lactan (and suitable corresponding lactone) can consider to be used for the synthetic of above-mentioned formula I compound.The locational similar alcohol functional group of carbonyl can be for epoxide open loop, aziridine open loop, with amine or be the suitable halid sulfonamide derivatives of pure nucleophilic reagent displacement, perhaps more like being suitable ketone reductive derivative.These ketone compounds also are that the present invention is interested especially.

Nedenskov etc. are at Acta Chem.Scand., and the described monobactam of 12:1405-1410 (1958) is represented by following formula: R wherein ¹And R ²Be exemplified as alkyl, aryl or alkenyl (as allyl group).

Sakakida etc. are at Bull.Chem.Soc.Japan, and the monobactam that contains second azo-cycle atom described in the 44:478-480 (1971) is represented by following formula:

Wherein R's is exemplified as CH ₃-or PhCH ₂-.

Hu etc. are at Tetrahedron Lett., and 36 (21): the monobactam with hydroxyl replacement described in the 3659-3662 (1995) is represented by following formula: Wherein R's is exemplified as benzyl (comprising cis and trans hydroxyl lactam).

Hoffman etc. describe the direct method that is prepared N-replacement 5-8 membered lactams by corresponding ketone at Tet.Lett. among the 30:4207-4210 (1989).These lactan are represented by following formula:

Wherein R is alkyl, alkenyl, alkynyl group, cycloalkyl or benzyl.

Vedejs etc. are at Tet.Lett., and 33:3261-3264 (1992) describes and prepares N-methoxyl group lactan by pimelinketone and dimethoxy amine.These structures are represented by following formula:

Comprise that by all means van der Steen etc. is at Tetrahedron, 47,7503-7524 (1991) 56, Hart etc. are at Chem Rev., and the amino aza cyclo-butanone derivatives of replacement 3-of those approach preparations of describing in the document of 89:1447-1465 (1989) and wherein citation is represented by following formula:

R wherein ¹And R ²Independently be selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl base, aryl, heteroaryl, heterocyclic radical or combination and form cyclic group.

Lowe etc. describe cyclosubstituted lactan at Bioorg.Med.Chem.Lett. among the 4:2877-2882 (1994), and are represented by following formula:

R wherein ²And R ³Be exemplified as aryl and substituted aryl, R ¹Be exemplified as alkyl or hydrogen.

McKennis, Jr. etc. describe among the 28:383-387 (1963) by the synthetic 3-aminopyrrolidone that replaces of alpha-brominated ketone at J.Org.Chem..These compounds are represented by following formula:

R wherein ¹Be aryl or heteroaryl, R ²Corresponding to corresponding amine R ²-NH ₂Any substituting group that can exist.

The other reference of the amino lactan synthetic of α is as follows:

1.Shirota Deng at J.Med.Chem., describe the synthetic of following formula: compound among the 20:1623-1627 (1977):

2.Overberger Deng at J.Am.Chem.Soc, describe the preparation of the Beta-methyl hexanolactam of following formula optically active among the 85:3431 (1963):

3.Herschmann at Helv.Chim.Acta, the Beckman that describes among the 32:2537 (1949) by piperitone resets synthetic two replacement hexanolactams, this lactan is represented by following formula:

4.Overberger Deng at Macromolecules, describe among the 1:1 (1968) by synthetic 8 membered lactams of 3-methyl suberone, as follows:

5.Busacca Deng at Tet.Lett., report benzo lactan (benzo-aza ketone) is synthetic among the 33:165-168 (1992):

Croisier etc. are at United States Patent (USP) the 4th, 080, and the report following formula: compound is synthetic in No. 449 J.A.Robl etc. are at Tetrahedron Lett., and 36 (10): encircle the benzyl lactan three shown in below 1593-1596 (1995) report prepares with interior Friedel-Crafts sample cyclisation, and wherein Pht is the phthaloyl imino blocking group:

Flynn etc. disclose another tricyclic lactam series at J.Med.Chem. in the reference of 36:2420-2423 (1993) and citation.

6.Orito Deng at Tetrahedron, the open benzo-aza ketone that replaces by the phenyl of following formula representative among the 36:1017-1021 (1980): Wherein R is H or CH ₃-.

Kawase etc. disclose the N-methoxyl group benzo azatropylidene ketone by the following formula representative at J.Org.Chem. among the 54:3394-3403 (1989):

7.Lowe Deng at J.Med.Chem., describe several route of synthesis of the replacement benzo azatropylidene ketone of following formula among the 37:3789-3811 (1994): R wherein ¹Be substituted aryl or cyclohexyl, X is suitable substituting group, R ²Can be H or alkyl.Yet, syntheticly be suitable for multiple R by what Lowe described ¹The substituting group form.

8.Robl Deng at Bioorg.Med.Chem.Lett., the reference of 4:1789-1794 (1994) and citation and Skiles etc. are disclosed among the 3:773-778 (1993) and contain other heteroatomic benzo lactan in the lactam nucleus at Bioorg.Med.Chem.Lett..These compounds are represented by following formula: Wherein X is O, R ²Be H or CH ₃, perhaps X is S, R ²Be H.In each case, R ¹Be H or alkyl.And in the article of Skiles, the thio group of thio lactam is oxidized to SO ₂Group.At J.Med.Chem., the Beckmann that describe in 39 (18): 3539 (1996) reset and also provide these structures by Grunewald etc.

9.Thomas Deng at J.Chem.Soc., Perkin II also provides the synthetic of the assorted lactan series of benzo that produces following formula: compound in 747 (1986):

X＝O，H ₂

R=CO ₂R wherein X is O or H ₂, R is CO ₂R.

10.Warshawsky Deng at Bioorg.Med.Chem.Lett., the other example of the benzo-aza ketone of open following formula among the 6:957-962 (1996):

Can summarize this synthetic R of generation is alkyl or aryl.

11.Ben-Ishai Deng at Tetrahedron, description can obtain benzo lactan synthetic of several following formulas among the 43:439-450 (1987): N=0,1 or 2 wherein, R=-CH ₃, PhCH ₂-and H.

12.van Niel etc. are at Bioorg.Med.Chem.Lett., the report following formula: compound is synthetic among the 5:1421-1426 (1995): Wherein X be-OH ,-NH ₂Or-NR ⁶R ⁶, R wherein ⁶Identical with above-mentioned definition.The ketone of report is general synthetic intermediate, can modify it by ordinary method such as reduction amination, reduction etc.

13.Kawase Deng at J.Org.Chem., describe the synthetic method of preparation following formula: compound among the 54:3394-3403 (1989):

Except above-mentioned points, also imagine saturated dicyclo alpha-amino group lactan and can be used for synthetic compound of formula i.This type of saturated dicyclo alpha-amino group lactan is well known in the art.Can.J.Chem. such as Edwards for example, describe several synthetic methods of the bicyclic lactam of following formula among the 49:1648-1658 (1971):

Equally, Milligan etc. are at J.Am.Chem.Soc., and the lactan of report following formula is synthetic in the reference of 117:10449-10459 (1995) and citation:

R wherein ¹And R ²For H or-CH ₃, ring A can have 6-13 atom, and ring B can have 5-7 atom.R can be alkyl, aryl, cycloalkyl etc.

Curran etc. are at Tet.Lett., disclose among the 36:191-194 (1995) to lactam nucleus condensed saturated rings structure in introduce heteroatomic method, he has described the synthetic method of the lactan that can be used to obtain following formula:

Slusarchyk etc. are at Bioorg.Med.Chem.Lett., also disclose among the 5:753-758 (1995) to lactam nucleus condensed saturated rings structure in introduce heteroatomic method, he describes the synthetic method of the lactan that can obtain following formula:

Wyvratt etc. in european patent application 61187 (1982), also disclose to lactam nucleus condensed saturated rings structure in introduce heteroatomic method, he describes the lactan of following formula:

Cornille etc. are at J.Am.Chem.Soc., are described in and have other heteroatomic lactan in the cyclic lactam structure (except that the nitrogen-atoms of the amido of lactan) among the 117:909-917 (1995), and he describes the lactan of following formula:

J.Kolc.Coll.Czech.Chem.Comm., it is the lactan with assorted lactam nucleus atom that 34:630 (1969) description Methionin is suitable for cyclisation, is shown below: Wherein X is O, S and NR, is as alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic radical etc. at this R.

Equally, the J.Org.Chem. of Dickerman etc., 14:530 (1949) ⁸⁶, Dickerman etc. J.Org.Chem., the J.Org.Chem. of 20:206 (1955) and Dickerman etc., everyone all uses Schmidt and the Beckmann reaction that replaces on the 4-piperidone among the 19:1855 (1954), obtains the lactan of following formula: Wherein R is acyl group, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic radical, and prerequisite is that R is not sour unsettled group, as t-Boc; R ' is hydrogen, alkyl, substituted alkyl, alkoxyl group, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic radical, heterocyclic oxy group, halo, cyano group, nitro, trihalomethyl group etc.

Hoffman etc. describe suitable quadrol acid amides intramolecular cyclization on ketone or aldehyde at J.Org.Chem. among the 27:3565 (1962), as follows:

R is methyl, phenyl

Wasserman etc. are at J.Am.Chem.Soc., 103:461-2 (1981) and Crombie etc. are at Tetrahedron Lett., 27 (42): among the 5151-5154 (1986) twice report will obtain containing the method for the bigger cyclic lactam of azepine group based on the ring expansion of beta-lactam.

Yokoo etc. described in the 29:631 (1956), prepare the azepine hexanolactam by asymmetric amine with the Dieckmann method at Bull.Chem.Soc.Jap., and are as follows: Wherein R is identical with definition in this reference.The disclosure of Yokoo etc. can be expanded to and comprise that R is the situation of alkyl, substituted alkyl, aryl, alkoxyl group, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic radical, alkenyl, substituted alkenyl base etc.

Burkholder etc. have reported the synthetic of various oxa-lactan series members at Bioorg.Med.Chem.Lett. in the document of 2:231 (1993) and citation thereof, wherein the oxa-lactan can be represented by following formula:

Wherein ' R is identical with definition in this reference, and R can be alkyl, substituted alkyl, aryl, alkoxyl group, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic radical, alkenyl, substituted alkenyl base etc.

Freidinger etc. have reported synthetic (general available identical method prepares the oxa-lactan) of thia lactan at J.Org.Chem. among the 47:104-109 (1982), he reports the preparation of the thia lactan of following formula: This reference provides a series of be adapted at that R in the above-mentioned formula can be by any amine (alkylamine, arylamine, heteroaryl amine etc.) deutero-lactan synthetic, and it is restricted to the R group and does not contain any functional group (as primary amine and secondary amine) with formaldehyde reaction.The general synthesis flow that is provided by Freidlinger etc. is:

Described coupling reagent is for any standard reagent of use in general peptide bond or amido linkage form, as carbodiimide reagent.Also referring to as Karanewsky at United States Patent (USP) the 4th, 460, No. 579 and Kametani etc. are at Heterocycles, described in the 9:831-840 (1978).

The expansion of Friedinger method can be obtained down two of array structure and replace the thia lactan:

In the method, described thio lactam is by being prepared as follows:

In actual terms, R ²To be limited to aryl and heteroaryl, and the sterically hindered alkyl such as the tertiary butyl.R ¹For can be highly changeable, only being subjected to subsequently, reactions steps limits.

Other method is the Kametani method, and this method can obtain following lactan: In principle, the Kametani method allows R ¹And R ²The group range of choice is very wide, mainly is subjected to the restriction to stable reaction conditions.

Referring to as Yanganasawa etc. at J.Med.Chem., 30:1984-1991 (1987) and J.Das etc. are at Biorg.Med.Chem.Lett., described in the 4:2193-2198 (1994), introduced the isomery 7-unit thia lactan synthetic universal method of time array structure: Article one, route of synthesis is: R ²Can be (as alkyl, substituted alkyl, aryl, heteroaryl, the heterocyclic radical etc.) of alterable height, this be owing to exist by aldehyde and Nitromethane 99Min. synthesizing nitryl ethidene derivant (Henry reaction), the number of ways of dewatering subsequently.R ¹Be limited to the group that can experience alkylated reaction.

In this building-up reactions, R ²It can be alterable height.Introduce R ²Desired raw material can be alcohol derivate, form methanesulfonates subsequently and easily obtain by reducing any known α-BOC-amino acid.

As mentioned above, the main path of lactan preparation carries out Beckmann/Schmidt ring expansion reaction for adopting the various intermolecular or intramolecularly approach that encircle the lactan of size of preparation.The intramolecularly approach produces lactan nitrogen and participates in ring condensed dicyclo material.The other approach of aforesaid method is based on the intramolecular cyclization that is structured in the omega-amino acid/ester that takes place before the cyclisation of substituting group type wherein, and the intramolecular cyclization of electrophilic center cyclisation on the nucleophilic functional group, back one cyclisation is as the cyclisation at center as described in the Friedel Crafts type of carrying out in the Ben-Ishal method of preparation benzo-aza ketone.A kind of method in back is applicable to multiple heteroaromatics and benzene type ring, also goes for producing two keys of non-aromatics or triple bond that substituting group widely or ring condense arrangement.

With reagent as diborane, lithium aluminum hydride etc. to as described in lactan carry out deoxidation and can obtain azo-heterocyclic compound (=X is a dihydro).

Equally, when U=H, OH, can be by the epoxidation of cycloalkenyl group, prepare this compounds with advance the capable Evil third ring open loop as ammonia subsequently.After forming formula I compound (=U is H), the OH oxidation can be obtained naphthenic one (=X is an oxo).

In addition, can be used for the present invention's 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone derivatives with ordinary method and reagent preparation.For example, at first, can make uncle N--Boc-2-amino-the 2 '-methyl diphenyl based compound cyclisation of suitable replacement, generate corresponding 5 by handling biphenyl compounds with about 2.1-about 2.5 normal highly basic such as s-butyl lithium, 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone derivatives.This reaction generally in inert diluent such as THF, in approximately-80 ℃ to carrying out in-60 ℃ of temperature ranges approximately.Then, under about-78 ℃, the dianion with dry carbon dioxide treatment produces obtains 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.This method by R.D.Clark etc. at Tetrahedron, 49 (7), further describe in the document of 1351-1356 (1993) and citation.

5, after 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketogenesis, in inert diluent such as DMF, at first handle dibenzo azatropylidene ketone with about 1.1 to about 1.5 normal highly basic such as sodium hydride, can easily make the amide nitrogen alkylation.This reaction was generally carried out about 0.5 to about 6 hours to about 80 ℃ of temperature at about-10 ℃.The negatively charged ion that makes generation then contacts with excessive (being preferably about 1.1 to about 3.0 equivalents) alkylogen, and this alkylogen is generally alkyl chloride, alkyl bromide or alkyl iodide.Generally speaking, this is reflected at about 0 ℃ and carried out about 1 to about 48 hours to about 100 ℃ of temperature.

Then, use ordinary method and reagent at 7-alkyl-5,5 of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone add amino.For example, at highly basic as 1,1,1,3,3,3-hexamethyldisilazane (KHMDS) exists down, handles 7-methyl-5,7-dihydro-6H-dibenzo [b with excessive butyl nitrite, d] azatropylidene-6-ketone, obtain 5-oximido-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.In the presence of catalyzer such as palladium charcoal, the hydro-reduction oximido obtains 5-amino-7-methyl-5 subsequently, 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.Also can use other conventional aminating method, shift, subsequently azido-be reduced as trinitride.

Equally, can prepare with ordinary method and reagent and be applicable to various benzodiazepine derivative of the present invention.For example; by at first forming the acyl chlorides of glycine derivative with oxalyl chloride; then in the presence of alkali such as 4-methylmorpholine; make above-mentioned acyl chlorides and the coupling of 2-Uvinul A Plus; the 2-Uvinul A Plus is coupled on α-(iprotiazem base)-N-(carbobenzoxy) glycine, obtains 2-[α-(iprotiazem base)-N-(carbobenzoxy) glycyl]-Uvinul A Plus.In the presence of the mercury chloride (II) of excessive (preferred about 1.1 to about 1.5 equivalents), handle this compound with ammonia, obtain 2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl] Uvinul A Plus.Can easily make this intermediate cyclisation by handling then, obtain 3-(carbobenzoxy) amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine -2-ketone with glacial acetic acid and ammonium acetate.Subsequent removal Cbz group obtains 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine -2-ketone.

Perhaps, with conventional trinitride shift reaction, subsequently the azido-reduction of generation to be formed corresponding amino, can easily make 2,3-dihydro-5-phenyl-1H-1, the 3-position amination of 4-benzodiazepine -2-ketone.The condition of these reactions and correlated response is described in the following example.In addition, can be with ordinary method and reagent easily 2,3-dihydro-5-phenyl-1H-1, the 1-position alkylation of 4-benzodiazepine -2-ketone.For example, generally at first by in inert diluent such as DMF, with about 1.1 to about 1.5 normal alkali such as sodium hydride, potassium tert.-butoxide, 1,1,1,3,3,3-hexamethyldisilazane potassium, cesium carbonate processing benzodiazepine ketone carry out this reaction.This reaction generally approximately-78 ℃ carried out about 0.5 to about 6 hours to about 80 ℃ of temperature.The negatively charged ion of generation is contacted with the alkylogen of excessive (preferred about 1.1 to about 3.0 equivalents), and described alkylogen is generally alkyl chloride, alkyl bromide or alkyl iodide.This reaction was generally carried out about 1 to about 48 hours at about 0 ℃ to about 100 ℃.

In addition, the 3-amino-2 of Shi Yonging in the present invention, 4-dioxo-2,3,4, generally by at first making propanedioic acid and 1, the coupling of 2-phenylenediamine is prepared for 5-tetrahydrochysene-1H-1,5-benzodiazepine .The condition of this reaction is well known in the art, describes in as PCT application WO 96-US8400960603.Carry out alkylation and amination with ordinary method and reagent subsequently, obtain various 3-amino-1, two (alkyl)-2 of 5-, 4-dioxo-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .These class methods describe in further detail in the following example.

Therefore, can obtain a large amount of lactan, lactone and thiolactone with methods known in the art.Equally, there are many examples that are used for the synthetic amino compound cycloalkyl of above-mentioned formula I compound this area.

With above-mentioned synthetic method synthetic compound of formula i the time, raw material may contain chiral centre (as L-Ala), and therefore, when using the racemize raw material, the product of generation is R, the mixture of S enantiomorph.Perhaps, the chiral isomer of raw material can be used,, chiral product can be obtained so if the reaction scheme of using does not make this raw material racemization.This type of reaction scheme can comprise the conversion of chiral centre in synthetic.

Therefore, except that other explanation, otherwise product of the present invention is diastereomer or R, the mixture of S enantiomorph.Yet when the needs chiral product, this chiral product is corresponding to the L-amino acid derivative so preferably.Perhaps, chiral product can obtain by purification technique, and described technical point is from diastereomer or enantiomorph, so that one or another kind of steric isomer to be provided.This type of technology is well-known in the art.Medicinal preparations

When as medicine, formula I compound gives with the form of medicinal compositions usually.These compounds can give by all means, comprise oral, rectum, approach in skin, subcutaneous, vein, intramuscular and nose.These compounds all are effective as injectable composition and oral compositions.The mode that this compounds is known with pharmacy field prepares, and comprises at least a active compound.

The present invention also comprises medicinal compositions, and described medicinal compositions contains one or more and the pharmaceutically acceptable carrier-bound above-mentioned formula I compound as active ingredient.In preparation composition of the present invention,, seal with a kind of vehicle dilution or with the carrier of capsule, sachet, paper or other vessel form usually with described active ingredient and a kind of mixed with excipients.When this vehicle was used as thinner, it can be solid, semisolid or fluent material, and it can be as solvent, carrier or the medium of this active ingredient.Therefore, described composition can be for tablet, pill, pulvis, lozenge, sachet, cachet, elixir, suspension agent, emulsion, solution, syrup, aerosol (as solid or in liquid medium), contain for example pulvis of ointment, soft hard-gelatin capsules, suppository, aseptic parenteral solution and the sterile packed of the active compound of as many as 10% (weight).

In formulation preparation, with may need to grind this active compound before other component is mixed, so that suitable granularity to be provided.If this active compound is insoluble basically, then be ground into usually less than 200 purpose granularities.If this active compound is water miscible basically, then regulate granularity by grinding usually, in preparation, to provide the distribution of basic homogeneous, for example about 40 orders.

Some example of appropriate excipients comprises lactose, glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, sterilized water, syrup and methylcellulose gum.Described preparation can also comprise: lubricant, such as talcum powder, Magnesium Stearate and mineral oil; Wetting agent; Emulsifying agent and suspension agent; Sanitas is such as methyl hydroxybenzoate and nipasol; Sweeting agent and taste-additive.Can prepare the present composition,, provide quick-release, slowly-releasing or the extended release of this active ingredient so that after adopting methods known in the art to give this patient.

Described composition is preferably with unit dosage preparation, and each dosage contains the about 100mg of the 5-that has an appointment, more commonly is the active ingredient of the about 30mg of about 10-.Term " unit dosage " is meant that being suitable as single dose is used for the mammiferous unit independently physically of human subject and other, and each unit contains the active substance that calculates the predetermined amount that produces required result of treatment and suitable pharmaceutical excipient.Preferably, use with following formula I compound with about 20% (weight) that is not higher than medicinal compositions, more preferably no higher than about 15% (weight), surplus is a medicinal inert carrier.

This active compound effectively, gives with medicinal significant quantity in very wide dosage range usually.Yet, should be appreciated that the actual administered dose of this compound will be by the doctor according to comprising that following correlative factor determines: age, body weight and the reaction of disease to be treated, the route of administration of selection, actual administered compound, individual patient, the seriousness of this patient's symptom etc.

When the solids composition of preparation such as tablet, main active ingredient is mixed with pharmaceutical excipient, form the solid preformulation composition of the homogeneous mixture that contains The compounds of this invention.When claiming that these preformulation composition are homogeneous, mean that this active ingredient is dispersed in the said composition, make said composition can easily be further divided into the unit dosage of same validity, such as sheet, ball and capsule.This solid preformulation thing and then be divided into the unit dosage of the above-mentioned type contains for example 0.1 to about 500mg active ingredient of the present invention.

Can be to tablet of the present invention or coating of pill, perhaps carry out compound, so that the formulation that obtains prolongation effect advantage to be provided.For example, this tablet or pill can comprise an internal dose component and outside dosage component, and the latter is the capsule form on the former.These two components can be isolated by the enteric layer as anti-disintegration under one's belt, and make internal composition complete by entering duodenum, or delay to discharge.Can use multiple material to be used for this class enteric layer or dressing, this class material comprises the mixture of multiple polymeric acid and polymeric acid, such as lac, hexadecanol and rhodia.

Can add novel composition of the present invention and be used for the liquid form of oral or drug administration by injection, comprise the aqueous solution, suitably syrup, water-based or the oily suspensions and the emulsion of using the edible oil flavoring such as Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil and elixir and similar pharmaceutical carrier of flavoring.

The composition that is used for sucking or be blown into is included in solution and the suspension and the pulvis of pharmaceutically acceptable water-based or organic solvent or its mixture.The liquid or solid composition can contain suitable pharmaceutically acceptable vehicle mentioned above.Preferably give described composition, to be used for part or systemic effect by oral or nasal respiration approach.Composition in the solvent of preferred pharmaceutical compositions can utilize rare gas element to atomize.Atomized soln can directly suck from atomisation unit, maybe this atomisation unit can be connected to face shield (face masks tent) or intermittent type positive pressure respirator.Preferably give solution, suspension or powder composite from device per os or the intranasal that discharges said preparation in a suitable manner.

Following example of formulations illustrates medicinal compositions of the present invention.

Example of formulations 1 preparation contains the hard gelatin capsule of following component: group component

(mg/ capsule) active ingredient 30.0 starch 305.0 Magnesium Stearates 5.0 mix above component, and are filled in the hard gelatin capsule with the loading amount of 340mg.

Example of formulations 2 adopts following component to prepare tablet: group component

(mg/ sheet) active ingredient 25.0 Microcrystalline Celluloses 200.0 colloid silicas 10.0 stearic acid 5.0 mix above component, and compacting forms tablet, every heavy 240mg.

Example of formulations 3 preparations contain the dry powder inhaler formulations of following component: composition weight % active ingredient 5 lactose 95 mix this active ingredient with lactose, and mixture is added in the dry powder suction unit.

Example of formulations 4

Be prepared as follows tablet, every contains the 30mg active ingredient:

Group component

(mg/ sheet)

Active ingredient 30.0mg

Starch 45.0mg

Microcrystalline Cellulose 35.0mg

Polyvinylpyrrolidone 4.0mg

(as 10% solution in the sterilized water)

Sodium starch glycolate 4.5mg

Magnesium Stearate 0.5mg

Talcum powder 1.0mg

Amount to 120mg

Make active ingredient, starch and Mierocrystalline cellulose by 20 order U.S. sieve and thorough mixing.With the powder mixes of polyvinylpyrrolidonesolution solution and generation, then it is passed through 16 order U.S. sieves.So the particle that produces is in 50 ℃ of-60 ℃ of dryings, and by 16 order U.S. sieves.Then, sodium starch glycolate, Magnesium Stearate and the talcum powder by 30 order U.S. sieves in advance added in the particle, mix the back and on tabletting machine, suppresses, produces every tablet of heavily tablet of 150mg.

Example of formulations 5

Be prepared as follows every capsule that contains the 40mg medicine:

Group component

(mg/ capsule)

Active ingredient 40.0mg

Starch 109.0mg

Magnesium Stearate 1.0mg

Amount to 150.0mg

Active ingredient, starch and Magnesium Stearate are mixed,, and be filled in the hard gelatin capsule with the amount of 150mg by 20 order U.S. sieves.

Example of formulations 6

Be prepared as follows every suppository that contains the 25mg active ingredient:

Group component

Active ingredient 25mg

Saturated fatty acid glyceride to 2,000mg

Make active ingredient pass through 60 order U.S. sieves, be suspended in the saturated fatty acid glyceride of using minimum required heat melts in advance.Then mixture is injected the suppository mold of 2.0g labelled amount, allow its cooling.

Example of formulations 7

Be prepared as follows the suspension agent that every 5.0ml dosage contains the 50mg medicine:

Group component

Active ingredient 50.0mg

Xanthan gum 4.0mg

Xylo-Mucine (11%)

Microcrystalline Cellulose (89%) 50.0mg

Sucrose 1.75g

Sodium Benzoate 10.0mg

Correctives and tinting material are an amount of

Pure water is to 5.0ml

Active ingredient, sucrose and xanthan gum are mixed,, mix with Microcrystalline Cellulose and carboxymethylcellulose sodium solution in the previously prepared water then by 10 order U.S. sieves.Sodium Benzoate, correctives and tinting material add while stirring with some water dilutions.Add enough water then, produce volume required.

Example of formulations 8

Group component (mg/ capsule)

Active ingredient 15.0mg

Starch 407.0mg

Magnesium Stearate 3.0mg

Amount to 425.0mg

Active ingredient, starch and Magnesium Stearate are mixed,, and be filled in the hard gelatin capsule with the amount of 560mg by 20 order U.S. sieves.

Example of formulations 9

Be prepared as follows the subcutaneous preparation of using:

Group component

Active ingredient 1.0mg

Semen Maydis oil 1ml

(, if desired, in said preparation, can use about 5.0mg of as many as or more active ingredient) according to the stability of this active ingredient in Semen Maydis oil.

Example of formulations 10

Be prepared as follows topical preparation:

Group component

Active ingredient 1-10g

Emulsifying wax 30g

Whiteruss 20g

Paraffinum molle alba is to 100g

Paraffinum molle alba is heated until fusing.Add whiteruss and emulsifying wax and stirring until dissolving.Add active ingredient and continue and stir, until dispersion.Cooling mixture is until curing then.

Another the preferred preparation that is used for the inventive method adopts through skin transfer device (" patch ").Can provide The compounds of this invention with the continuous or discontinuous infusion of manipulated variable with this class transdermal patch.The structure and the use of transmitting the transdermal patch of medicine are well-known in the art.Referring to the United States Patent (USP) 5,023,252 of for example authorizing on June 11st, 1991, this patent is attached to herein by reference.Can prepare this class patch is used for continuously, intermittently or discharge medicine on request.

Usually need or must directly or indirectly this medicinal compositions be introduced brain.Direct technology is usually directed to the useful for drug delivery intubate is placed host's ventricular system, to walk around hemato encephalic barrier.At United States Patent (USP) 5,011, described being used for biological factor is transported to a this implantable transfer system of individual particular anatomical region in 472, this patent is attached to herein by reference.

The Indirection techniques of general preferred use is usually directed to prepare described composition, promptly by hydrophilic medicament is converted into fat-soluble medicine, so that the drug latenciation effect to be provided.Generally by protecting hydroxyl, carbonyl, sulfuric ester and the primary amine group that exists on this medicine, giving this medicine stronger fat-soluble, and easier in the hemato encephalic barrier transhipment, and reach latentiation.Perhaps, can instantaneously open the hypertonic solution of hemato encephalic barrier, to strengthen the transmission of hydrophilic drugs by endoarterial infusion.

Can be at Remington ' s pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, PA finds in the 17th edition (1985) that other is applicable to preparation of the present invention.Purposes

Compound of the present invention and medicinal compositions can be used to suppress the release of beta amyloid peptide and/or it is synthetic, and therefore comprises in the human Mammals Alzheimer having practicality in treatment.

As mentioned above, compound as herein described is applicable to all said medicine transfer systems.In addition, give compound intravital serum half-life in order to increase, can be with described compound packing, introduce in the lipid body cavity, be prepared as colloid, maybe can adopt other routine techniques to prolong the serum half-life of described compound.Can utilize various methodologies, the preparation liposome as the United States Patent (USP) 4,235,871,4,501,728 and 4,837 at for example Szoka etc., is described in 028, and these patents all are attached to herein by reference.

The amount that gives patient's compound changes with following factor: treat administered compound, such as administration purpose, the patient's of prevention or treatment state, administering mode etc.In treatment is used, give to suffer from the patient of AD with composition, administered dose is enough to suppress to small part the further outbreak of this disease and complication symptom thereof.The amount that is suitable for finishing this purpose is defined as " treatment effective dose ".To depend on the judgement of attending doctor according to some factors for the effective amount of this purposes, described factor comprises such as the degree of this patient AD or seriousness, this patient's age, body weight and general situation etc.When as therapeutical agent, best dosage range with the about 500mg/kg/ of about 1-days gives compound described herein.

In prophylactic application, composition there is the patient who develops into AD (for example determining by genetic screening or family's characteristic) risk, its administered dose is enough to suppress the outbreak of this disease symptoms.The amount that is suitable for finishing this purpose is defined as " prevention effective dose ".Significant quantity for this purposes will depend on the judgement of attending doctor according to some factors, described factor such as this patient age, body weight and general situation etc.When using as prophylactic agent, best dosage range with the about 500mg/kg/ of about 1-days gives compound described herein.

As mentioned above, the compound that gives the patient is above-mentioned medicinal compositions form.These compositions can be sterilized by conventional sterilising technology, or can filtration sterilization.Aqueous solution former state packing can be used, also can freeze-drying, freeze-dried preparation mixes with the sterile aqueous solvent before administration.The pH of described compound formulation is generally 3-11, and more preferably 5-9 most preferably is 7-8.Should be appreciated that, use some above-mentioned vehicle, carrier or stablizer will cause forming pharmaceutical salts.

Compound described here also is applicable to and gives cell with diagnosis and discovery medicine with these compounds.Specifically, these compounds can be used for the diagnosis that cell discharges and/or synthesizes beta amyloid peptide.In addition, compound described here can be used to measure and estimate the inhibition activity that other drug candidate pair cell discharges and/or synthesizes beta amyloid peptide.

Provide following synthetic embodiment and biology embodiment with explanation the present invention, these embodiment should not be construed as by any way and limit the scope of the invention.

Embodiment

In following examples, below abbreviation has following implication.If a not definition of abbreviation, then it has generally accepted implication.

BEMP=2-tert-butyl imino--2-diethylin-1, the 3-dimethyl is complete

Hydrogen-1,3,2-diaza phosphorine

Boc=tert-butoxycarbonyl

BOP=benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus six

Fluorophosphate

Bd=wide bimodal

Bs=wide unimodal

D=bimodal

Dd=double doublet

DIC=di-isopropyl carbodiimide

DCM=methylene dichloride

DMF=dimethyl formamide

DMAP=dimethyl aminopyridine

DMSO=dimethyl sulfoxide (DMSO)

EDC=ethyl-1-(3-dimethylaminopropyl) carbodiimide

Eq.=equivalent

EtOAc=ethyl acetate

EtOH=ethanol

G=gram

HOBT=I-hydroxybenzotriazole hydrate

HunigShi alkali=diisopropylethylamine L=rise m=multimodal M=molar concentration max=maximum meq=milliequivalent mg=milligram/mL=milliliter mm=millimeter mmol=mM MOC=methoxyl group oxygen base carbonyl N=normal N/A=do not obtain ng=nanogram nm=nanometer OD=optical density PEPC=1-(3-(1-pyrrolidinyl) propyl group)-3-ethyl carbodiimides PP-HOBT=piperidines-piperidines-I-hydroxybenzotriazole psi=pounds/square inch φ=phenyl q=quartet quint=quintet rpm=rev/min s=unimodal t=three peaks TFA=trifluoroacetic acid THF=oxolane tlc=thin-layer chromatography μ L=microlitre

UV=ultraviolet

In addition, below abbreviation is used for showing the commercial source of some compound and reagent: Aldrich=Aldrich Chemical Company, Inc., 1001 West

Saint?Paul?Avenue，Milwaukee，WI?53233

USAFluka??????????????＝??Fluka?Chemical?Corp.，980?South?2nd?Street，

Ronkonkoma?NY?11779?USALancaster??????????＝??Lancaster?Synthesis?Inc.，P.O.Box?100

Windham，NH?03087?USASigma??????????????＝??Sigma，P.O.Box?14508，St?Louis?MO?63178

USAChemservice????????＝??Chemsertice?Inc.，Westchestet，PABachem?????????????＝??Bachem?Biosciences?Inc.，3700?Horizon

Drive，Renaissance?at?Gulph?Mills，King?of

Prussia，PA?19406?USAMaybridge??????????＝??Maybridge?Chemical?Co.Trevillett，Tintagel，

Comwall?PL34?OHW?United?KingdomTCI????????????????＝??TCI?America，9211?North?Harborgate?Street，

Portland?OR?97203Alfa???????????????＝??Johnson?Matthey?Catalog?Company，Inc.30

Bond?Street，Ward?Hill，MA?01835-0747Novabiochem????????＝??Calbiochem-Novabiochem?Corp.10933?North

Torrey?Pines?Road，P.O.Box?12087，La?Jolla

CA?92039-2087Oakwood????????????＝??Oakwood，Columbia，South?CarolinaAdvanced?Chemtech??＝??Advanced?Chemtech，Louisville，KYPfaltz?&?Bauer?????＝??Pfaltz?&?Bauer，Waterbury，CT，USA

In the following example, all temperature are degree centigrade (except that specializing).Each compound that provides among the embodiment 1-can prepare with one of following universal method.

Universal method A

EDC coupling-method I

Under nitrogen atmosphere, in THF, stir carboxylic acid (1.0eq.), I-hydroxybenzotriazole hydrate (1.1eq.) and amine (1.0eq.).In this mixture, add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.1eq.), adding suitable alkali then, (if use unhindered amina, then is 1.1eq. alkali such as HunigShi alkali, if the use amine hydrochlorate then is a 2.1eq. alkali).In stirring at room after about 4 to 17 hours, removal of solvent under reduced pressure.Resistates distributes between ethyl acetate and water, separates organic phase, order sodium bicarbonate aqueous solution, dilute hydrochloric acid solution and salt water washing.Dry then organic layer (sodium sulfate), concentrating under reduced pressure.Be not further purified and use this product, perhaps adopt standard method to carry out purifying, described standard method such as silica gel column chromatography and/or recrystallization.

Universal method B

EDC coupling-method II

In suitable solvent (such as THF, diox or DMF), stir carboxylic acid (1eq.), add alcohol or oxime (1-5eq.).In this mixture, add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.2eq.) and I-hydroxybenzotriazole hydrate (1eq.), add suitable alkali then, such as 4-methylmorpholine, triethylamine or HunigShi alkali (0-1eq.).The 4-dimethylaminopyridine that adds catalytic amount (0.1eq.) then, this mixture stirs down in room temperature and exsiccant nitrogen atmosphere, after 20 hours, this mixture of concentrating under reduced pressure, the enriched material of generation distributes between ethyl acetate and water.Separate organic phase, with sodium bicarbonate aqueous solution and salt water washing, dry (sodium sulfate) then, and concentrating under reduced pressure.Be not further purified and use this crude product product, perhaps adopt standard method to carry out purifying, described standard method such as silica gel column chromatography and/or recrystallization.

Universal method C

EDC coupling-method III

Under 0 ℃, nitrogen atmosphere, in the THF solution (0.08-0.06M) of amine (1eq.), add 3,5-difluorophenyl acetic acid (1.10eq.), I-hydroxybenzotriazole hydrate (1.15-1.20eq.), N, N-diisopropylethylamine (2.30eq.) adds 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.15-1.20eq.) then.Remove cooling bath, allow the mixture temperature, stirred simultaneously 12-14 hour to room temperature.Dilute this solution with ethyl acetate then, with 0.2-0.5M HCl (2 *) aqueous solution, rare sodium bicarbonate (1 *) and salt solution (1 *) washing, then through the dried over sodium sulfate organic phase, filter, vacuum concentration by flash chromatography purifying resistates, obtains this product then.

Universal method D

Remove uncle N--BOC blocking group-method I

In round-bottomed flask, be cooled to the middle trifluoroacetic acid (0.07-0.08M) that adds of tetrahydroglyoxaline (1eq.) of 0 ℃ N-Boc protection, add phenylmethylether (6.2-8.0eq.) then.The solution of product was stirred 1 hour in 0 ℃, allow its temperature then, stirred simultaneously 1-1.15 hour to room temperature.Vacuum concentrated solution adds ether then, and mixture is vacuum concentration once more.Resistates is dissolved in methylene dichloride or the ethyl acetate,, uses salt solution (1 *) washing sometimes,, filter and vacuum concentration, obtain this product then through the dried over sodium sulfate organic phase with sodium bicarbonate dilute aqueous soln (1 or 2 *) washing.

Universal method E

Remove uncle N--BOC blocking group-method II

Uncle N--Boc-amine is dissolved in the suitable dry solvent (such as 1,4-diox or ethyl acetate), solution is cooled off in ice bath.Gas HCl is by in the solution, saturated with HCl until mixture, stir the mixture then, intact until raw material consumption.The mixture that concentrating under reduced pressure produces produces described amine hydrochlorate.Described amine hydrochlorate need not be further purified and use or grind in ether, and filters and collect the solid that produces.

Universal method F

Synthetic-method the I of thiazoline

Under nitrogen atmosphere, in the absolute ethyl alcohol and stirring solution of nitrile (1eq.), add 2-mercaptoethylamine (1-3eq.).With the reaction mixture refluxed heating, run out of then until this nitrile.Concentrating under reduced pressure mixture then, the product that produces by chromatography and/or recrystallization purifying.

Universal method G

Synthetic-method the II of thiazoline

Under nitrogen atmosphere, in the absolute ethyl alcohol and stirring solution of nitrile (1eq.), add L-ethylcysteine hydrochloride (1-3eq.) (Aldrich) and the N of stoichiometric quantity, N-diisopropylethylamine (based on described L-ethylcysteine hydrochloride).With reaction mixture refluxed heating 3 hours, concentrating under reduced pressure then.Product by chromatography and/or crystallization purifying generation.

Universal method H

With the cyclisation of Burgess reagent

To N-[N-(3; the 5-dichlorophenyl)-the L-alanyl]-L-serine methylester (178mg; 0.5mmol) 2.5ml THF solution in add 147mg (0.62mmol; 1.2eq.) indifferent salt hydroxide (methoxycarbonyl sulphonamide) three second ammoniums (derive from Aldrich Chemical Co.; Milwaukee, Wiconsin).Solution was refluxed 5 hours again, then in stirring at room 36 hours.Remove then and desolvate, resistates uses 3: 2 hexane/ethyl acetate as eluent by preparation property tlc purifying, obtains 50mg 2-[(S)-1-(3,5-dichlorobenzene amido) ethyl]-(S)-and 4-methoxycarbonyl-2-oxazolidine, be yellow oil.Can adopt this method, (the amino acid)-L-serine ester that is replaced by N prepares various other (S)-4-alkoxy carbonyl-2-oxazolidines.

Universal method I

5-aminoalkyl group-1,2,4-oxadiazole synthetic

According to above universal method B the amino acid and the amidoxim of uncle N--Boc protection are reacted, corresponding O-acyl group oxime is provided.With O-acyl group oxime reflux in dimethylbenzene, azeotropic removal of water obtains the 5-aminoalkyl group-1,2 that uncle N--Boc protects then, and 4-oxadiazole derivative carries out purifying by silica gel column chromatography then usually.Remove uncle-Boc blocking group according to above universal method E then, obtain 5-aminoalkyl group-1,2, the 4-oxadiazole.

Following examples A-L explanation can be used for preparing heterocycle intermediate synthetic of The compounds of this invention.

Embodiment A

(S)-and 5-(1-aminoethyl)-3-ethyl-1,2,4-oxadiazole hydrochloride synthetic

According to above universal method I, prepare title compound with the uncle N--Boc-L-L-Ala (Sigma) and third amidoxim.

Embodiment B

(S)-and 5-(1-amino-2-styroyl)-3-methyl isophthalic acid, 2,4-oxadiazole hydrochloride synthetic

According to above universal method I, prepare title compound with uncle N--Boc-L-phenylalanine (Sigma) and second amidoxim.

Embodiment C

(S)-and 5-(1-amino-1-phenmethyl)-3-methyl isophthalic acid, 2,4-oxadiazole hydrochloride synthetic

According to above universal method I, prepare title compound with uncle N--Boc-L-phenylglycocoll (Sigma) and ethamine oxime.

Embodiment D

(S)-and 5-(1-amino-1-phenmethyl)-3-phenyl-1,2,4-oxadiazole hydrochloride synthetic

According to above universal method I, prepare title compound with uncle N--Boc-L-phenylglycocoll (Sigma) and benzene first amidoxim.

Embodiment E

(S)-and 5-(1-amino-1-phenmethyl)-3-(4-mehtoxybenzyl)-1,2,4-

Synthesizing of oxadiazole hydrochloride

According to above universal method I, prepare title compound with uncle N--Boc-L-phenylglycocoll (Sigma) and 4-anisole second amidoxim.

Embodiment F

(2S)-and 2-(1-aminoethyl)-5 (R, S)-ethoxycarbonyl-2-oxazoline synthetic

Steps A-N-carbonyl benzyloxy-L-L-Ala-D, L-isoserine ethyl ester

According to above universal method A, with N-carbonyl benzyloxy-L-L-Ala (Sigma) and D, L-isoserine carbethoxy hydrochloride, preparation title compound.

Step B-(2S)-2-[1-(N-carbonyl benzyloxy) aminoethyl]-5 (R, S)-ethoxycarbonyl

Synthesizing of-2-oxazoline

To the N-of above steps A carbonyl phenoxy group-L-L-Ala-D, add triphenylphosphine (2eq.) in the anhydrous THF solution of L-isoserine ethyl ester.Mixture is cooled to 0 ℃, drips diethylazodicarboxylate's (2eq.) THF solution.Allow the mixture temperature that produces to room temperature, after 20 hours, this mixture of concentrating under reduced pressure.Produce oily matter by the silica gel column chromatography purifying, produce title compound oily matter, this oily matter uses without being further purified.

Step C-(2S)-2-(1-aminoethyl)-5 (R, S)-ethoxycarbonyl-2-oxazoline synthetic

The crude product oily matter of above step B is dissolved in the ethanol,, under nitrogen atmosphere, stirs the solution degassing.Add palladium carbon (10%), replace nitrogen atmosphere with the hydrogen under the gasbag pressure.Mixture was stirred 2 hours, pass through diatomite filtration then.Filtrate is concentrated, and resistates provides title compound oily matter by the silica gel column chromatography purifying.

Embodiment G

(S)-and 2-(1-aminoethyl)-4 (R, S)-ethoxycarbonyl-2-thiazoline hydrochloride synthetic

Steps A-(S)-2-[1-(N-tert-butyl ester base) aminoethyl]-the 4-ethoxycarbonyl

Synthesizing of-2-thiazoline

According to C.D.J.Boden etc., Synlett, method described in 5,417 (1995), preparation title compound.

Step B-(S)-2-(1-aminoethyl)-4 (R, S)-ethoxycarbonyl-2-

Synthesizing of thiazoline hydrochloride

Adopt above universal method E, remove the uncle N--Boc blocking group of above steps A product, obtain title compound.

Embodiment H

Synthesizing of 2-(3,5-difluoro phenmethyl)-4-carboxyl-2-thiazoline

Synthesizing of steps A-2-(3,5-difluoro phenmethyl)-5-ethoxycarbonyl-2-thiazoline

According to universal method G, adopt 3,5-difluorophenyl acetonitrile and L-ethylcysteine hydrochloride (Aldrich), preparation title compound.

Synthesizing of step B-2-(3,5-difluoro phenmethyl)-5-carboxyl-2-thiazoline

According to above universal method II-A-method B, the above steps A product of Shi diox liquid hydrolysis with 1 equivalent LiOH obtains title compound.

Example I

Synthesizing of N-(3,5-difluoro phenylacetyl) phenyl glycinonitrile (glycinonitrile)

According to above universal method A, adopt 3,5-difluorophenyl acetic acid (Aldrich) and 2-phenyl glycinonitrile hydrochloride (Lancaster), preparation title compound.Crude product is by the silica gel column chromatography purifying, and the ethyl acetate/hexane that adopts 1: 1 is as eluent, crystallization from 1-chlorobutane/acetonitrile then.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝3.61(s，2H)，6.13(d，1H)，6.98(m，2H)，7.12(m，1H)，7.46(m，5H)，9.40(d，1H)。

C ₁₆H ₁₂F ₂N ₂O (MW=286.28); Mass spectrum (M ⁺) 286.

Embodiment J

Synthesizing of 2-(1-aminoethyl)-1-tert-butyl ester base-4-methoxycarbonyl-4-phenmethyl-2-tetrahydroglyoxaline

Steps A-1-[2-(N-carbonyl benzyloxy) amino-sulfo-propionyl] piperidines synthetic

According to Gilbert etc., Tetrahedron, 1995,51, method described in the 6315-6336 adopts N-carbonyl benzyloxy-D, and L-L-Ala (Sigma) prepares title compound (total yield 51%) solid in two steps, and fusing point is 68-69 ℃.By tlc monitoring end reaction (Rf=0.59 launched among the DCM/EtOAc at 24: 1), product is by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.37-7.29(m，5H)，6.46(bd，1H，J＝8.26Hz)，5.10(Ab _q，2H，J _AB＝12.38Hz，Δν _AB＝9.12Hz)，4.92(p，1H，J＝7.07Hz)，4.41-4.34(m，1H)，4.17-4.06(m，1H)，3.86-3.65(m，2H)，1.75-1.65(bm，6H)，1.35(d，3H，J＝6.75Hz)。

C ₁₆H ₂₂N ₂O ₂S (MW=306.43); Mass spectrum (MH ⁺) 306.2.

Step B-2,3-diamino-2-phenmethyl methyl propionate synthetic

According to Gilbert etc., Tetrahedron, 1995,51, method described in the 6315-6336 adopts L-phenylalanine methyl ester hydrochloride (Aldrich), divides three steps preparation title compound (total yield 14%).By tlc monitoring end reaction (Rf=0.26 launched among the DCM/MeOH at 9: 1), product is by rapid column chromatography purifying, recrystallization from cyclohexane/ethyl acetate (20: 1) then.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.32-7.17(m，3H)，7.14-7.09(m，2H)，3.70(s，3H)，2.96(AB _q，2H，J _AB＝13.13Hz，Δν _AB＝114.63Hz)，2.90(AB _q，2H，J _AB＝13.38Hz，Δν _AB＝86.35Hz)，1.55(bs，4H)。

C ₁₁H ₁₆N ₂O ₂(MW=208.26); Mass spectrum (MH ⁺) 209.1.

Step C-2-[1-(N-carbonyl benzyloxy) amino-ethyl)-4-methoxycarbonyl-4-phenmethyl

Synthesizing of-2-tetrahydroglyoxaline

Above steps A product (1 equivalent) in the methyl iodide (35 equivalent) is heated to backflow 8 hours under nitrogen.With the dark yellow solution for vacuum concentration is golden yellow foam, removes any residual methyl iodide with methyl alcohol (2 *) azeotropic then.Resistates is dissolved in the methyl alcohol (0.2M), adds the product (1 equivalent) of above step B.Under nitrogen, the transparent colourless solution that produces is heated to and refluxed 1 hour, in stirring at room 14 hours, be heated to once more and refluxed 1 hour then.Allow solution be cooled to room temperature, then vacuum concentration.By tlc monitoring reaction (Rf=0.27 launched among the DCM/MeOH at 95: 5), residue provides the mixture as 1: 1 diastereomer compound (75% yield) by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.36-7.20(m，8H)，7.14-7.08(m，2H)，5.84-5.74(m，1H)，5.15-5.02(m，2H)，4.96(bs，1H)，4.44-4.30(m，1H)，4.03-3.97(m，1H)，3.72-3.66(m，1H)，3.70(s，1.5H)，3.69(s，1.5H)，3.07(AB _q，1H，J _AB＝13.38Hz，Δν _AB＝54.25Hz)，3.06(AB _q，1H，J _AB＝13.51Hz，Δν _AB＝52.03Hz)，1.39(d，1.5H，7.00Hz)，1.35(d，1.5H，J＝7.00Hz)。

C ₂₂H ₂₅N ₃O ₄(MW=395.46); Mass spectrum (MH ⁺) 396.1.

Step D-1-tert-butyl ester base-2-[1-(N-carbonyl benzyloxy) aminoethyl]-the 4-methoxycarbonyl

Synthesizing of-4-phenmethyl-2-tetrahydroglyoxaline

Above step C product under room temperature (1.815g, THF 1eq.) (9ml)/H ₂In 1: 1 mixture of O (9ml), add sodium bicarbonate (0.377g, 1.50eq.) and tert-Butyl dicarbonate (1.304g, 2.00eq.) THF of (Aldrich) (6ml) solution.The light yellow mixture that under room temperature, stir to produce 1 hour, and then add sodium bicarbonate among the THF (3ml) (0.188g, 0.75eq.) and tert-Butyl dicarbonate (0.652g, 1.00eq.), with mixture restir 1 hour.Mixture dilutes with ethyl acetate then, wash with salt solution (2 *), through dried over sodium sulfate, filter and vacuum-drying, and, adopt 3: 2 hexane/EtOAc as eluent through the rapid column chromatography purifying, the viscosity oily matter of title compound is provided, yield 77% (Rf=0.31 launched among hexane/EtOAc at 3: 2).Racemic product is separated as 1: 1 non-enantiomer mixture.

The NMR data are as follows:

¹H-nmr(DMSO-d ₃，250MHz)：δ＝7.38-7.09(m，10H)，6.00(bd，1H，J＝7.75Hz)，5.21-5.05(m，3H)，4.15(d，1H，J＝11.76Hz)，4.08(d，1H，J＝11.26Hz)，3.85-3.80(m，2H)，3.78(s，3H)，3.20-3.00(m，2H)，1.43(s，9H)，1.36(d，1.5H，J＝6.75Hz)，1.24(d，1.5H，J＝6.75Hz)。

C ₂₇H ₃₃N ₃O ₆(MW=495.58); Mass spectrum (MH ⁺) 496.4.

Step e-1-tert-butyl ester base-2-(1-aminoethyl)-4-methoxycarbonyl

Synthesizing of-4-phenmethyl-2-tetrahydroglyoxaline

Under atmosphere of hydrogen, with Pd (OH) on the amine of the racemize N-Cbz of the above step D of (0.010-0.015M) among MeOH protection and 20% carbon ₂The mixture jolting of (20% weight eg.) 4 hours.By the Celite pad filtration catalizer,, provide the viscosity oily matter (Rf=0.26 launched among the DCM/MeOH at 95: 5) of title compound with the filtrate vacuum concentration.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.32-7.15(m，5H)，4.19-4.05(m，2H)，3.87-3.78(m，1H)，3.80(s，3H)，3.21-3.03(m，2H)，2.98(bs，2H)，1.43(s，9H)，1.33(d，1.5H，J＝7.00Hz)，1.26(d，1.5H，J＝6.50Hz)。

C ₁₉H ₂₇N ₃O ₄(MW=361.44); Mass spectrum (MH ⁺) 361.

Embodiment K

Synthesizing of 2-(1-aminoethyl)-1-tert-butyl ester base-4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline

Steps A-2,3-diamino-2-phenylpropionic acid methyl esters synthetic

According to Gilbert etc., Tetrahedron, 1995,51, method described in the 6315-6336 adopts (S)-(+)-2-phenyl glycine methyl ester hydrochloride (Aldrich), divides three steps preparation title compound (total yield 16%).By tlc monitoring end reaction (Rf=0.34 is 9: launch among the 1DCM/MeOH), product is by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.52-7.47(m，2H)，7.39-7.25(m，3H)，3.74(s，3H)，3.42(d，1H，J＝13.26Hz)，2.89(d，1H，J＝13.26Hz)，1.88(bs，4H)。

C ₁₀H ₁₄N ₂O ₂(MW=194.23); Mass spectrum (MH ⁺) 195.

Step B-2-[1-(N-carbonyl benzyloxy) amino-ethyl)-4-methoxycarbonyl-4-phenyl

Synthesizing of-2-tetrahydroglyoxaline

(36.5ml, 38eq.) (5.206g 1.1eq) is heated to backflow 16 hours to the embodiment J steps A product under nitrogen with methyl iodide.With the dark yellow solution for vacuum concentration is golden yellow foam, once removes any residual methyl iodide with methyl alcohol (30ml) component distillation then.Resistates is dissolved in the methyl alcohol (30ml), add above steps A product (3.00g, 1eq.).Under the nitrogen pale yellow solution that produces is heated to backflow 3.5 hours.Allow solution be cooled to room temperature, vacuum concentration by the flash chromatography purifying, produces the title compound (5.08g, 86%) as 1: 1 racemize non-enantiomer mixture.(Rf=0.32 was at 95: 5 CH by the tlc monitoring reaction ₂Cl ₂Launch among/the MeOH), product is by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.38-7.28(m，10H)，6.09-6.00(m，1H)，5.11-5.04(m，2H)，4.10(bs，1H)，3.84-3.68(m，4H)，1.53(d，3H，J＝7.00Hz)。

C ₂₀H ₂₃N ₃O ₄(MW=381.43); Mass spectrum (MH ⁺) 382.4.

Step C-1-tert-butyl ester base-2-(1-(N-carbonyl benzyloxy) aminoethyl]-the 4-methoxycarbonyl

Synthesizing of-4-phenyl-2-tetrahydroglyoxaline

THF under room temperature (35ml)/H ₂Above step step B product among the O (35ml) (4.94g, 1eq.) in, add sodium bicarbonate (2.00g, 1.84eq.) and tert-Butyl dicarbonate (7.50g, 2.65eq.) (Aldrich).The light yellow mixture that under room temperature, stir to produce 1 hour, and then add sodium bicarbonate (0.45g, 0.41eq.) and tert-Butyl dicarbonate (0.98g, 2.65eq.), with mixture restir 1 hour.Mixture dilutes with ethyl acetate then, and water (1 *), salt solution (2 *) washing through dried over sodium sulfate, are filtered and vacuum concentration, and through the rapid column chromatography purifying.Racemize diastereomer product [Rf=0.38 (as the isomer A of racemic mixture) and 0.28 (as the isomer B of racemic mixture), with 6: 1 toluene/EtOAc wash-outs] separate by flash chromatography, adopt 6: 1 toluene/EtOAc to 5: the step gradient of 1 toluene/EtOAc is as the eluent wash-out, 2 groups of racemize enantiomorphs-isomer A (1.122g) viscosity oily matter and isomer B (1.0868g) white solid are provided, and yield is 73%.

NMR data following (isomer A):

¹H-nmr(CDCl ₃，250MHz)：δ＝7.39-7.27(m，10H)，6.20(bd，1H，J＝8.00Hz)，5.40-5.30(m，1H)，5.13(s，2H)，4.84(d，1H，J＝11.26Hz)，3.87(d，1H，J＝11.26Hz)，3.70(s，3H)，1.52-1.50(m，12H)。

C ₂₆H ₃₁N ₃O ₆(MW=481.55); Mass spectrum (MH ⁺) 482.3.

Step D-1-tert-butyl ester base-2-(1-aminoethyl)-4-methoxycarbonyl

Synthesizing of-4-phenyl-2-tetrahydroglyoxaline

Under atmosphere of hydrogen (35-40psi), with Pd (OH) on the isomer A of the above step C of (0.010-0.015M) in the methyl alcohol and 20% carbon ₂Jolting 4 hours.Filter the removal catalyzer by Celite pad,,, provide title compound (88%) viscosity oily matter (Rf=0.28 launched among the DCM/MeOH at 95: 5) through the flash chromatography purifying with the filtrate vacuum concentration.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.43-7.27(m，5H)，4.80(d，1H，J＝11.26Hz)，4.41(q，1H，J＝6.75Hz)，3.87(d，1H，J＝11.51Hz)，3.73(s，3H)，2.02(s，2H)，1.49(s，9H)，1.45(d，3H，J＝6.75Hz)。

C ₁₈H ₂₅N ₃O ₄(MW=347.42); Mass spectrum (MH ⁺) 348.2.

Embodiment L

(4R)-4-carboxyl-2-(3,5-difluoro phenmethyl)-4-methyl-2-thiazoline synthetic

Steps A-3,5-difluoro phenylacetyl imido acid methyl ester hydrochloride synthetic

According to S.C.Zimmerman etc., J.Org.Chem.1989,54, be used for the method for synthetic imido-ester, preparation title compound described in the 1256-1264.Specifically, make anhydrous HCl air-flow feed 3,5-difluorophenyl acetonitrile (5.045g, 1eq.) (Lancaster) and methyl alcohol (2.00ml, ether 1.5eq.) (100ml) solution 20 minutes in 0 ℃.Under room temperature nitrogen, allow the solution temperature to room temperature then, during forming white precipitate, stirred 23 hours.Filter and collect white precipitate, with the ether flushing, produce title compound (6.6756g, 91%) solid, fusing point is 156.5-157.5 ℃.

The NMR data are as follows:

¹H-nmr(CDCl ₃，300MHz)：δ＝13.01(bs，1H)，11.93(bs，1H)，7.04-6.97(m，2H)，6.83-6.75(m，1H)，4.30(s，3H)，4.08(s，2H)。

Synthesizing of step B-(R)-2-methyl acthiol-J hydrochloride

According to G.Pattenden etc., Tetrahedron, 1993,49, method described in 2131-2138 and the reference wherein quoted, by D-(S)-acthiol-J hydrochloride with 5 steps preparation title compound viscosity oily matter (35% total recovery).According to J.E.Baldwin etc., Tetrahedron, 1989,45, method described in the 4537-4550, by D-cysteine hydrochloride monohydrate (Aldrich) with 1 step (98% yield) preparation D-(S)-acthiol-J hydrochloride.

The NMR data are as follows:

¹H-nmr(D ₂O，250MHz)：δ＝4.83(bs，4H)，3.92(s，3H)，3.27(d，1H，J＝15.26Hz)，3.02(d，1H，J＝15.01Hz)，1.69(s，3H)。

Specific rotation: [α] ₂₀=2.44 (c, 1.15, H ₂O)

C ₅H ₁₂NO ₂SCl (MW=185.67); Mass spectrum (MH ⁺) 149.1.Synthesizing of step C-(4R)-2-(3,5-difluoro phenmethyl)-4-methoxycarbonyl-4-methyl-2-thiazoline

According to G.Pattenden etc., Tetrahedron, 1995,51, be used for the method for synthetizing thiazolium quinoline, preparation title compound described in the 7313-7320.Specifically, CH under room temperature ₂Cl ₂(the R)-2-methyl acthiol-J hydrochloride (1.7109g of above step B (55ml), 1.00eq.) in, add above steps A the imido-ester hydrochloride (2.042g, 1.00eq.), in 20 minutes, drip then triethylamine (1.28ml, 1.00eq.).Opaque, the pale yellow solution that produce were stirred under room temperature 40 hours, form canescence suspension during this period.Mixture dilutes with methylene dichloride, with 1N dilute hydrochloric acid (1 *), water (1 *) and salt solution (1 *) washing; Organic phase is filtered and vacuum concentration through dried over mgso then, and resistates is through the rapid column chromatography purifying, adopt 20: 1 DCM/EtOAc as eluent, obtain title compound (1.6669g, 63%) colorless oil (Rf=0.34 launched among the DCM/EtOAc at 20: 1).

The NMR data are as follows:

¹H-nmr(CDCl ₃，300MHz)：δ＝6.85-6.79(m，2H)，6.74-6.67(m，1H)，3.81(s，2H)，3.80(s，3H)，3.79(d，1H，J＝11.30Hz)，3.17(d，1H，J＝11.30Hz)，1.56(s，3H)。

Specific rotation: [α] ₂₀=3.71 (c, 1.02, CHCl ₃).

C ₁₃H ₁₃NO ₂SF ₂(MW=285.32); Mass spectrum (MH ⁺) 285.2.

Step D-(4R)-4-carboxyl-2-(3,5-difluoro phenmethyl)-4-methyl-

Synthesizing of 2-thiazoline

Under room temperature, to 1, (0.726g drips LiOH (0.0671g, 1.1eq.) solution in the water (1ml) in 1.0eq.) to the above step C product in the 4-diox (15ml) in 2 minutes.Add entry (2ml) again, the opaque colourless solution that produces was stirred under room temperature 1.25 hours, solution becomes transparent and colourless during this period.To about 5ml, concentrated solution dilutes with ethyl acetate with solution for vacuum concentration, with 1N dilute hydrochloric acid (2 *) and water (1 *) washing; Through dried over sodium sulfate, filter and vacuum concentration then, produce title compound (0.6111g, yield 88%) white solid, fusing point is 119.5-122.0 ℃.

The NMR data are as follows:

¹H-nmr(CDCl ₃，300MHz)：δ＝10.88(bs，1H)，6.86-6.78(m，2H)，6.76-6.69(m，1H)，3.89(AB _q，2H，J _AB＝15.14Hz，Δν _AB＝20.57Hz)，3.84(d，1H，J＝11.48Hz)，3.21(d，1H，J＝11.61Hz)，1.61(s，3H)。

The explanation of following universal method II-A to II-E and example II-A to II-S can be used for preparing carboxylic acid intermediate synthetic of The compounds of this invention.

Universal method II-A

Ester is hydrolyzed to free acid

Make ester be hydrolyzed to free acid with ordinary method.It below is 2 the example that this class routine is taken off the ester method.

Method A: to CH ₃OH/H ₂Add the normal salt of wormwood of 2-5 in the carboxylicesters in 1: 1 mixture of O.With mixture heating up to 50 ℃ 0.5-1.5 hour, finish until tlc demonstration reaction.Reactant is cooled to room temperature, on rotatory evaporator, removes methyl alcohol.The pH of all the other aqueous solution is transferred to about 2, add ethyl acetate to extract product.Organic phase is with saturated NaCl solution washing then, and through dried over mgso.Get on to desolventize at rotatory evaporator, produce product.

Method B: amino acid ester is dissolved in diox/water (4: 1), adds LiOH soluble in water (about 2eq.), make that adding the back total solvent is about 2: 1 dioxs: water.Stirred reaction mixture is finished until reaction, and diox is removed in decompression.Residue is soluble in water and wash with ether.Separate each layer, water layer is acidified to pH2.Use the ethyl acetate extraction water layer.Acetic acid ethyl ester extract filters the back decompression and removes solvent through dried over sodium sulfate.Resistates ordinary method (for example recrystallization) purifying.

Universal method II-B

The preparation of acyl ammonia

With 3, (30g, 0.174mol) (Aldrich) is dissolved in the methylene dichloride 5-difluorophenyl acetic acid, and this solution is cooled to 0 ℃.Add DMF (0.5ml, catalytic amount), in 5 minutes, drip then oxalyl chloride (18ml, 0.20mol).Reactant was stirred 3 hours, and the rotary evaporation that reduces pressure then obtains oily matter, is placed on high vacuum pump last 1 hour, obtains 3,5-two fluorophenylacetyl chloride light yellow oil shape things.Other acyl chlorides can prepare in a similar manner.

Universal method II-C

The Schotten-Baumann method

With 3,5-two fluorophenylacetyl chlorides (deriving from universal method II-B) drop to 0 ℃ of L-L-Ala (Aldrich), and (16.7g, (215ml is 0.43mol) in the solution for 2N sodium hydroxide 0.187mol).In 0 ℃ reactant was stirred 1 hour, under room temperature, stir then and spend the night.Ethyl acetate (3 * 150ml) extractions are used in reactant water (100ml) dilution then.Organic layer is with salt solution (200ml) washing then, and through dried over mgso, the decompression rotary evaporation is to resistates.Recrystallization resistates from ethyl acetate/hexane obtains required product (34.5g, 82% yield).Other acyl chlorides can be used for this method, can be used for intermediate of the present invention to provide.

Universal method II-D

Reduction amination

Add 1 normal 2-oxo carboxylic acid ester (for example pyruvate) in the ethanolic soln of the arylamines in the hydrogenation bottle, add 10% palladium carbon (based on 25% (weight) of described arylamines) then.On Parr jolting device, reactant is in 20psi H ₂Following hydrogenation shows to react until tlc finishes (30 minutes to 16 hours).Make then in the reaction mixture and (derive from Aldrich Chemical Company, Inc.), get on to desolventize at rotatory evaporator by diatomite 545 pads.The crude product resistates is further purified by chromatography then.

Universal method II-E

The EDC couling process

In the dichloromethane mixture of 1: 1 corresponding carboxylic acid of 0 ℃ and corresponding amino acid ester or acid amides, add 1.5 equivalent triethylamines, add 2.0 equivalent hydroxybenzotriazole monohydrates then, add 1.25 equivalent ethyl-3-(3-dimethylamino) propyl carbodiimide diimmonium salt hydrochlorate then.Reaction mixture stirred under room temperature spend the night, be transferred in the separating funnel then.Mixture water, saturated sodium bicarbonate aqueous solution, 1N HCl and saturated NaCl solution washing are then through dried over mgso.The solution that produces gets on to desolventize at rotatory evaporator, produces crude product.

Example II-A

Synthesizing of N-(phenylacetyl)-L-L-Ala

Adopt universal method II-C, by phenyllacetyl chloride (Aldrich) and L-L-Ala (Aldrich) preparation title compound solid, fusing point is 102-104 ℃.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝9.14(br?s，1H)，7.21-7.40(m，5H)，6.20(d，J＝7.0Hz，1H)，4.55(m，1H)，3.61(s，2H)，1.37(d，J＝7.1Hz，3H)。

¹³C-nmr(CDCl ₃)：δ＝176.0，171.8，134.0，129.4，127.5，48.3，43.2，17.9。

Example II-B

Synthesizing of N-(3,5-difluoro phenylacetyl)-L-L-Ala

Adopt universal method II-C, by 3,5-two fluorophenylacetyl chlorides (universal method II-B) and L-L-Ala (Aldrich) preparation title compound.

The NMR data are as follows:

¹H-nmr(CD ₃OD)：δ＝8.32(bs?s，0.3H)，6.71(m，2H)，6.60(m，1H)，4.74(br?s，1.7H)，4.16(m，1H)，3.36(s，2H)，1.19(d，J＝7.3Hz，3H)。

¹³C-nmr(CD ₃OD)：δ＝175.9，172.4，164.4(dd，J＝13.0，245.3Hz)，141.1，113.1(dd，J＝7.8，17.1Hz)，102.9(t，J＝25.7Hz)，49.5，42.7，17.5。

Example II-C

Synthesizing of N-(cyclopentyl ethanoyl)-L-phenylglycocoll

The preparation of steps A-N-(cyclopentyl ethanoyl)-L-phenyl glycine methyl ester

Adopt above universal method II-E, by NSC 60134 (Aldrich) and L-phenyl glycine methyl ester hydrochloride (Novabiochem) preparation title compound solid, fusing point is 83-86 ℃.By silica gel tlc monitoring reaction (Rf=0.28 launches in 25% ethyl acetate/hexane), product is by recrystallization purifying from ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.35(s，5H)，6.44(bd，1H)，5.6(d，1H)，3.72(s，3H)，2.24(bs，3H)，1.9-1.4(m，6H)，1.2-1.05(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝172.3，171.7，136.7，129.0，128.6，127.3，56.2，52.7，42.5，36.9，32.40，32.38，24.8。

C ₁₆H ₂₁NO ₃(MW=275.35); Mass spectrum (M+Na) 298.

The preparation of step B-N-(cyclopentyl ethanoyl)-L-phenylglycocoll

Adopt above universal method II-A, by N-(cyclopentyl ethanoyl)-L-phenyl glycine methyl ester (deriving from steps A) preparation title compound solid, fusing point is 155-158 ℃.By silica gel tlc monitoring reaction (Rf=0.18 launches in 10% ethanol/methylene).

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.60(d，J＝7.8Hz，1H)，7.45(m，5H)，5.41(d，J＝7.2Hz，1H)，2.20(m，3H)，1.8-1.1(m，8H)。

¹³C-nmr(CDCl ₃)：δ＝172.3，172.0，137.5，128.7，128.1，127.8，56.2，40.9，36.8，31.8，24.5。

C ₁₅H ₁₉NO ₃(MW=261.32); Mass spectrum (M+Na) 284.

Example II-D

Synthesizing of N-(cyclopentyl ethanoyl)-L-L-Ala

The preparation of steps A-N-(cyclopentyl ethanoyl)-L-alanine methyl ester

Adopt above universal method II-E, by NSC 60134 (Aldrich) and L-alanine methyl ester hydrochloride (Sigma) preparation title compound solid, fusing point is 43-46 ℃.Carry out purifying by recrystallization from ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (being included in 1.30, the d of 3H), 11H).

¹³C-nmr(CDCl ₃)：δ＝173.7，172.5，52.1，47.6，42.3，36.8，32.15，32.14，18.0。

C ₁₁H ₁₉NO ₃(MW=213.28); Mass spectrum (MH ⁺) 214.

The preparation of step B-N-(cyclopentyl ethanoyl)-L-L-Ala

Adopt above universal method II-A, by N-(cyclopentyl ethanoyl)-L-alanine methyl ester (deriving from steps A) preparation title compound.By silica gel tlc monitoring reaction (Rf=0.18 launches in 10% ethanol/methylene).

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝12.45(bs，1H)，8.12(d，J＝7.2Hz，1H)，4.24(quint，J＝7.2Hz，1H)，2.14(m，3H)，1.8-1.4(m，6H)，1.29(d，J＝7.2Hz，3H)，1.2-1.0(m，3H)。

¹³C-nmr(DMSO-d ₆)：δ＝174.6，171.9，47.3，41.1，36.7，31.8，24.5，17.2。

C ₁₀H ₁₇NO ₃(MW=199.25); Mass spectrum (MH ⁺) N/A.

Example II-E

Synthesizing of N-(cyclopropyl ethanoyl)-L-L-Ala

The preparation of steps A-N-(cyclopropyl ethanoyl)-L-alanine methyl ester

Adopt above universal method II-E, by cyclopropyl acetate (Aldrich) and L-alanine methyl ester hydrochloride (Sigma) preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.15 launches in 25% ethyl acetate/hexane),, adopt 25% ethyl acetate/hexane to carry out purifying as eluent by rapid column chromatography.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.60(d，1H)，4.55(m，1H)，3.69(s，3H)，2.10(m，2H)，1.34(d，3H)，0.95(m，1H)，0.58(m，2H)，0.15(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝173.7，172.3，52.3，47.7，41.0，18.2，6.7，4.27，4.22。

C ₉H ₁₅NO ₃(MW=185.22); Mass spectrum (MH ⁺) N/A.

The preparation of step B-N-(cyclopentyl ethanoyl)-L-L-Ala

Adopt above universal method II-A, by N-(cyclopropyl ethanoyl)-L-alanine methyl ester (deriving from steps A) preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.27 launches in 10% ethanol/methylene).

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝8.18(d，1H)，4.25(m，1H)，2.08(m，2H)，1.30(d，3H)，1.00(m，1H)，0.50(m，2H)，0.19(m，2H)。

¹³C-nmr(DMSO-d ₆)：δ＝174.6，171.7，47.4，17.3，7.6，4.12，4.06。

C ₈H ₁₃NO ₃(MW=1 99.25); Mass spectrum (MH ⁺) N/A.

Example II-F

Synthesizing of N-(cyclopropyl ethanoyl)-L-phenylglycocoll

The preparation of steps A-N-(cyclopropyl ethanoyl)-L-glycine methyl ester

Adopt above universal method II-E, prepare the title compound solid by cyclopropyl acetate (Aldrich) and L-phenyl glycine methyl ester, fusing point is 74-76 ℃.By silica gel tlc monitoring reaction (Rf=0.61 launches in 50% ethyl acetate/hexane), product is by recrystallization purifying from ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.35(m，5H)，6.97(bd，J＝7.2Hz，1H)，5.59(d，J＝7.8Hz，1H)，3.71(s，3H)，2.17(m，2H)，1.05-0.95(m，1H)，0.62(m，2H)，0.20(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝171.9，174.6，136.6，129.0，128.5，127.2，56.1，52.7，41.0，6.9，4.37，4.33。

C ₁₄H ₁₇NO ₃(MW=247.30); Mass spectrum (MH ⁺) N/A.

The preparation of step B-N-(cyclopentyl ethanoyl)-L-phenylglycocoll

Adopt above universal method II-A, by N-(cyclopropyl ethanoyl)-L-phenyl glycine methyl ester (deriving from steps A) preparation title compound solid, fusing point is 152-157 ℃.By silica gel tlc monitoring reaction (Rf=0.23 launches in 10% ethanol/methylene), by recrystallization purifying from ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.47(d，J＝7.69Hz，1H)，7.35(m，5H)，5.34(d，J＝7.69Hz，1H)，2.10(m，2H)，0.90(m，1H)，0.40(m，2H)，0.10(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝172.3，171.8，137.6，128.7，56.2，7.7，4.0。

C ₁₃H ₁₅NO ₃(MW=233.27); Mass spectrum (MH ⁺) N/A.

Example II-H

N-(2-xenyl)-D, L-L-Ala synthetic

With the 2-phenylaniline (2g, 1.18mmol, Aldrich), (1.1eq. Aldrich) mixes, and is heated with stirring to 85 ℃ for triethylamine (1.2eq.) and 2 bromopropionic acid ethyl ester.After 7 days, mixture dilutes with chloroform, washes with water.Dry organic moiety, and concentrate generation oily matter, oily matter is by silica gel column chromatography (1: 1 dichloromethane/hexane) purifying.The oily matter that produces is dissolved in 1: 2 the water/diox mixture (200ml), adds LiOH (2eq.).After 2 hours, mixture is concentrated, produce oily matter, it is soluble in water.The aqueous solution washs with ether, transfers to pH3 with 5N HCl then, uses ethyl acetate extraction.Dry organic moiety, and concentrate generation oily matter, it by silica gel column chromatography (EtOAc) purifying, is produced title compound.

Example II-I

N-(phenyl-furazan-3-yl)-D, L-L-Ala synthetic

4-phenyl-furazan-3-base amine (Maybridge) and Pyruvic Acid Ethyl ester (Aldrich) are dissolved in the dehydrated alcohol.Add the platinum (5%) on the nitric sulfid, with the mixture that produces in 150 ℃ of hydrogenations (1000psi, H ₂) 8 hours.Reaction mixture concentrates filtrate decompression by diatomite filtration then.Resistates adopts chloroform as eluent by the silica gel column chromatography purifying, obtains the title compound ethyl ester.Adopt universal method II-A method B (LiOH/H then ₂The O/ diox) the described ethyl ester of hydrolysis obtains title compound.

Example II-L

S-(+)-3,5-difluoro amygdalic acid synthetic

Steps A-S-(±)-3, the preparation of 5-difluoro methyl mandelate

To 3, add ZnCl in methylene dichloride (100ml) solution of 5-difluorobenzaldehyde (Aldrich) ₂(6.7g 21.1mmol), forms slurry.(21.0g 211.2mmol) adds in this slurry lentamente will to be dissolved in cyaniding trimethyl silane in the methylene dichloride (100ml) in 0 ℃.The solution that produces was stirred under room temperature 4 hours.The reaction mixture dilute with water separates organic layer then.With the organic layer simmer down to resistates that merges., in 0 ℃ of dissolving resistates anhydrous HCl gas was fed in this solution 10 minutes with MeOH (200ml).After stirring 18 hours under the room temperature, be solid with solution concentration.Solid is dissolved in methylene dichloride/water, and water-based is partly used dichloromethane extraction.The organic layer salt water washing that merges is through anhydrous magnesium sulfate drying and simmer down to solid (37.4g, 87.6%), mp=77-78 ℃.

¹H-nmr(300MHz，CDCl ₃)：δ＝6.97(dd，J＝96Hz，J＝1.79Hz，2H)，6.74(dt，J＝8.82，J＝2.28Hz，1H)，5.14(d，J＝4.64Hz，1H)，3.78(s，3H)，3.54(d，J＝5.1Hz，1H)。

The preparation of step B-S-(+)-3,5 difluoro methyl mandelate

HPLC separates (±)-3 by preparation property chirality, and 5-difluoro methyl mandelate, generation fusing point are 70-71 ℃ white solid.

The NMR data are as follows:

C ₉H ₈F ₂O ₃(MW=202.17); Mass spectrum (M+NH ₄ ⁺) 220.0.

C ₉H ₈F ₂O ₃The analytical calculation value: C, 53.47; H, 3.99.Measured value: C, 53.40; H, 3.89.

The preparation of step C-S-(+)-3,5 difluoro amygdalic acid

With S-(+)-3, the 74%THF aqueous solution of 5-difluoro methyl mandelate (1eq.) is cooled to 0 ℃, handles with lithium hydroxide.In 0 ℃ after 40 minutes, finish through the TLC monitoring reaction.Content is transferred in the separating funnel, between methylene dichloride and saturated sodium bicarbonate aqueous solution, distributes.Water layer 0.5N NaHSO ₄Ethyl acetate extraction 3 times are used in acidifying.The extract salt water washing that merges through dried over sodium sulfate, is filtered and the simmer down to white solid, and its fusing point is 119-122 ℃. ¹H NMR and known 3,5-difluoro amygdalic acid data consistent.

Example II-M

Synthesizing of 2-azido--(3, the 5-difluorophenyl) acetate

Steps A: in the three-necked flask that has mechanical stirrer and nitrogen inlet tube, add 3,5-difluorophenyl acetic acid (Aldrich) and THF.To be cooled to-78 ℃ in the reaction mixture, add the 1.2eq. triethylamine, drip trimethyl-acetyl chloride (1.05eq.) then (Aldrich).During adding, temperature is remained on-78 ℃.Remove cooling bath then, substitute with ice bath.Allow temperature temperature to 0 ℃, continue to stir 1 hour.Then reaction mixture is cooled to again-78 ℃.In-78 ℃, to THF, triphenyl methane (catalysis are housed, 0.1% (mole)) and (S)-(-)-4-benzyl-2-oxazolidinedione (oxazolidione) (1.1eq.) in second flask of (Aldrich), drips n-butyllithium solution, remains unchanged until orange.This reaction mixture in-78 ℃ of stirrings 30 minutes, is imported in first kind of reaction mixture with intubate then.The mixture that produces was stirred the quencher of usefulness 2.2eq. acetate 1 hour in-78 ℃.Solvent is removed in decompression, resistates is dissolved in the methylene dichloride again, with this solution with water washing, then with the washing of 1M salt of wormwood.Organic layer filters and concentrates through dried over sodium sulfate then.Resistates is by LC 2000 chromatography purifications, with EtOAc/ hexane (15.85) wash-out.The oily matter that produces is made slurry in hexane, obtain white solid, collects white solid by filtering, and obtains (S)-(-)-3-(3,5-difluoro phenylacetyl)-4-benzyl-2-oxazolidinedione.

Step B: drip LiHMDS (1.05eq.) to being cooled in-78 ℃ the 20ml anhydrous THF solution of (S)-(-)-3-(3,5-difluoro phenylacetyl)-4-benzyl-2-oxazolidinedione (3.0mM), simultaneously temperature is remained in-78 ℃.Reaction mixture in-78 ℃ of stirrings 15 minutes, is added the 10ml THF solution of the azide trisyl (1.12eq.) of pre-cooled (60 ℃) then.With reaction mixture restir 10 minutes, with the quencher of 4.4eq. acetate.Use warm water bath, with temperature rise to 30-40 ℃ 6 hours.Then reaction mixture is injected separating funnel, use dichloromethane extraction.Organic layer washs successively with bicarbonate solution, salt solution, through dried over sodium sulfate, filters and removes and desolvate.Resistates obtains 2-azido--2-(3, the 5-difluorophenyl) methyl acetate through LC 2000 chromatography purifications.

Step C: to the THF/H that is cooled to 2-azido--2-(3, the 5-difluorophenyl) methyl acetate of 0 ℃ ₂Add the 1.7eq. lithium hydroxide in O (2.6: the 1) solution.Reaction mixture was stirred under room temperature 3 hours, inject separating funnel then.Water extraction mixture washs with ether.Water layer 1N HCl acidifying, and use ethyl acetate extraction.Organic layer water and salt water washing then.Organic layer filters and concentrating under reduced pressure through dried over sodium sulfate, produces 2-azido--2-(3, the 5-difluorophenyl) acetate.

Example II-N

(R)-and N, N '-two-BOC-2-hydrazinepropionic acid synthetic

Steps A: (S)-(-)-4-benzyl-2-oxazolidone (oxazolidanone) in being cooled to-50 ℃ THF drips 1.1eq. n-Butyl Lithium (1.6M hexane solution) in (Aldrich).Allow in the reaction mixture temperature to-20 ℃, and then be cooled to-78 ℃, add propionyl chloride (1.1eq) 1 time.With reaction mixture in-78 ℃ of restir 15 minutes, then with its temperature to room temperature.Ethyl acetate extraction is used in reactant saturated sodium bicarbonate solution quencher then.Organic extract washes with water, uses the salt water washing then, and through dried over sodium sulfate, filters and concentrate, and produces (S)-(-)-3-propionyl-4-benzyl-2-oxazolidone.

Step B: in the THF solution of-78 ℃ (S)-(-)-3-propionyl-4-benzyl-2-oxazolidone, drip KHMDS (1.05eq.) (Aldrich).Reaction mixture in-78 ℃ of stirrings 30 minutes, is added pre-cooled azo-2-carboxylic acid's di tert butyl carbonate (Aldrich) by intubate then.After 5 minutes, add 2.6eq. acetate.Reaction mixture dichloromethane extraction then, organic layer is with the washing of 1M potassiumphosphate.Organic layer filters and concentrates through dried over sodium sulfate then, produces (S)-(-)-3-[(R)-N, N '-two-BOC-2-diazanyl propionyl]-4-benzyl-2-oxazolidone.

Step C:, N '-two-BOC-2-diazanyl propionyl to 0 ℃ 8ml THF and (S)-(-)-the 3-[(R)-N in the 3ml water]-4-benzyl-2-oxazolidone (0.49mol) solution in, add LiOH (1.7eq.) and H ₂O ₂(3.0eq.), reaction mixture was stirred under room temperature 3 hours.Then reaction mixture is injected separating funnel, dilute with water.The aqueous mixture ethyl acetate extraction is acidified to pH2.0 with 1N HCl then, uses ethyl acetate extraction.Organic layer filters and the removal solvent through dried over sodium sulfate then, obtains (R)-N, N '-two-BOC-2-hydrazinepropionic acid, and the latter uses without being further purified.

Example II-O

3,5-difluorophenyl-alpha-oxo-acetate synthetic

Steps A: according to J.Org.Chem., 45 (14), method described in the 2883-2887 (1980), by 1-bromo-3,5-two fluorobenzene (Aldrich) preparation 3,5-difluorophenyl-alpha-oxo-ethyl acetate.

Step B: with universal method II-A (method B) hydrolysis 3,5-difluorophenyl-alpha-oxo-ethyl acetate obtains 3,5-difluorophenyl-alpha-oxo-acetate.

Example II-P

Synthesizing of cyclopentyl-Alpha-hydroxy acetate

Adopt Gibby, W.A.; Gubler, C.J.Biochmical Medicine 1982,27, method described in the 15-25, (CAS 872-53-7 Wiley) divides 2 steps preparation title compound (CAS 6053-71-0) by cyclopentyl formaldehyde.

Example II-Q

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala

Adopt the 3rd, 598, No. 859 (its disclosure is whole by reference to be attached to herein) middle methods that propose of United States Patent (USP), preparation N-(3, the 4-dichlorophenyl) L-Ala.Specifically, to 3, add entry (the about 0.06ml of every ml Virahol) in 4-dichlorphenamide bulk powder (1 equivalent) Virahol (about every mole 3, the 4-dichlorphenamide bulk powder 500ml) solution (Aldrich) and 2-chloropropionic acid (2 equivalent) (Aldrich).With this mixture temperature to 40 ℃, add sodium bicarbonate (0.25 equivalent) continuously, reflux 4-5 days then.After the cooling, reaction mixture is injected water, filter to remove unreacted 3, the 4-dichlorphenamide bulk powder.With concentrated hydrochloric acid filtrate is acidified to pH3-4, filters the precipitation that produces, washing is also dry, produces title compound, m.p.=148-149 ℃.

Example II-R

Synthesizing of N-(3, the 4-difluorophenyl) L-Ala

Adopt United States Patent (USP) the 3rd, 598, No. 859 and the method for above embodiment Q proposition, adopt 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich) preparation N-(3, the 5-difluorophenyl) L-Ala.

Example II-S

α-fluoro-3,5-difluorophenyl acetic acid synthetic

Steps A-3,5-difluoro methyl mandelate synthetic

To 3, fed HCl gas 10 minutes in the methanol solution of 5-difluoro amygdalic acid (Fluorochem).The reactant backflow is spent the night.Vacuum concentrated mixture is absorbed into resistates in the ethyl acetate then, with saturated sodium bicarbonate and salt water washing.Organic layer filters and concentrates through dried over sodium sulfate, produces title intermediate white solid.

C ₉H ₈F ₂O ₃(MW=202.17); Mass spectrum 202.

¹H-nmr(300Mhz，CDCl ₃)：δ＝7.00(2H，d，J＝6.58Hz)，6.76(1H，t，J＝8.86Hz，)，5.16(1H，d，J＝5.29Hz)，3.81(3H，s)，3.54(1H，d，J＝5.39Hz)。

Step B-α-fluoro-3,5-difluorophenyl acetic acid methyl esters synthetic

Fluoridize diethylamino sulphur (DAST) dichloromethane solution (1.1eq.) with three and be cooled to 0 ℃, add pre-cooled 3, the dichloromethane solution of 5-difluoro methyl mandelate (1eq.).Shift a small amount of dichloromethane rinse of bottle.After 15 minutes, remove cooling bath, with reaction mixture restir 40 minutes under room temperature.Mixture is injected on ice, separate each layer.Organic phase saturated sodium bicarbonate and salt water washing.Organic phase is filtered and is concentrated through dried over sodium sulfate.Resistates with 7% ethyl acetate/hexane wash-out, obtains title intermediate yellow oil through the HPLC purifying.

C ₉H ₇F ₃O ₂(MW=204.16); Mass spectrum 204.

C ₉H ₇F ₃O ₂The analytical calculation value: C, 52.95; H, 3.46.Measured value: C, 52.80; H, 3.73.

Step C-α-fluoro-3,5-difluorophenyl acetic acid synthetic

According to universal method II-A method B, adopt α-fluoro-3,5-difluorophenyl acetic acid methyl esters prepares title intermediate white solid, and its fusing point is 100-102 ℃.

C ₈H ₅F ₃O ₂(MW=190.13); Mass spectrum 190.

C ₈H ₅F ₃O ₂The analytical calculation value: C, 50.54; H, 2.65.Measured value: C, 50.47; H, 2.79.

Synthesizing of following examples 1-20 explanation The compounds of this invention.

Embodiment 1

(S)-5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-

The 2-styroyl]-the 3-methyl isophthalic acid, 2,4-oxadiazole synthetic

According to above universal method A; with N-(3,5-difluoro phenylacetyl)-L-L-Ala (example II-B) and (S)-5-(1-amino-2-styroyl)-3-methyl isophthalic acid, 2; 4-oxadiazole hydrochloride (Embodiment B) preparation title compound solid, its fusing point is 159-162 ℃.(Rf=0.6 is at 10%MeOH/CHCl by the tlc monitoring reaction ₃The middle expansion), product is used 7%MeOH/CHCl by the silica gel column chromatography purifying ₃As eluent, recrystallization purifying from 1-chlorobutane then.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝4.30(m，1H)，5.26(m，1H)。

C ₂₁H ₂₂F ₂N ₄O ₃(MW=428.44); Mass spectrum (MH ⁺) 428.

Embodiment 2

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-ethoxycarbonyl-2-thiazoline

Synthetic

According to above universal method A, with 3,5-difluorophenyl acetic acid (Aldrich) and (S)-2-(1-aminoethyl)-4-ethoxycarbonyl-2-thiazoline hydrochloride (embodiment G) preparation title compound semisolid.By tlc monitoring reaction (Rf=0.2 launched in the EtOAc/ hexane at 1: 1), with 1: the 1EtOAc/ hexane is as eluent, by the silica gel column chromatography purified product.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝1.33(t，3H)，1.44(t，3H)，3.55(s，2H)，3.60(m，2H)，4.37(m，2H)，4.85(m，1H)，5.05(m，1H)，6.46(t，1H)，6.74(t，1H)，6.84(d，2H)。

C ₁₆H ₁₈F ₂N ₂O ₃S (MW=356.39); Mass spectrum (MH ⁺) 356.

Embodiment 3

1-tert-butyl ester base-2-[1-(N-carbonyl benzyloxy) aminoethyl]-the 4-methoxycarbonyl-

Synthesizing of 4-phenmethyl-2-tetrahydroglyoxaline

Under room temperature, to product (1.815g, THF 1eq.) (9ml)/H of embodiment J step C ₂Add in 1: 1 mixture of O (9ml) sodium bicarbonate (0.377g, 1.50eq.) and tert-Butyl dicarbonate (1.304g, 2.00eq.) THF of (Aldrich) (6ml) solution.The light yellow mixture that produces was stirred under room temperature 1 hour, and then the adding sodium bicarbonate (0.188g, 0.75eq.) and tert-Butyl dicarbonate (0.652g, THF 1.00eq.) (3ml) solution was with mixture restir 1 hour.Mixture dilutes with ethyl acetate then, wash with salt solution (2 *), through dried over sodium sulfate, filter and vacuum concentration, by the rapid column chromatography purifying, as eluent, obtain title compound viscosity oily matter with 3: 2 hexane/EtOAc, yield is 77% (Rf=0.31 launched among hexane/EtOAc at 3: 2).1: 1 mixture of the racemize of diastereomer can not separate by flash chromatography.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆，250?MHz)：δ＝7.38-7.09(m，10H)，6.00(bd，1H，J＝7.75Hz)，5.21-5.05(m，3H)，4.15(d，1H，J＝11.76Hz)，4.08(d，1H，J＝11.26Hz)，3.85-3.80(m，2H)，3.78(s，3H)，3.20-3.00(m，2H)，1.43(s，9H)，1.36(d，1.5H，J＝6.75Hz)，1.24(d，1.5H，J＝6.75Hz)。

C ₂₇H ₃₃N ₃O ₆(MW=495.58); Mass spectrum (MH ⁺) 496.4.

Embodiment 4

1-tert-butyl ester base-2-[1-(3,5-difluorophenyl kharophen) ethyl]-the 4-methoxycarbonyl-

Synthesizing of 4-phenmethyl-2-tetrahydroglyoxaline

According to above universal method C, with 3,5-difluorophenyl acetic acid (Aldrich) and 1-tert-butyl ester base-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenmethyl-2-tetrahydroglyoxaline (embodiment J), preparation title compound amorphous solid.By tlc monitoring reaction (Rf=0.34 launched among hexane/EtOAc at 2: 1), by the rapid column chromatography purified product.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.28-7.20(m，3H)，7.16-7.12(m，1H)，7.07-7.03(m，1H)，6.91-6.80(m，3H)，6.77-6.67(m，1H)，5.35-5.21(m，1H)，4.17-4.05(m，1H)，3.86-3.79(m，1H)，3.79(s，3H)，3.55(s，1H)，3.52(s，1H)，3.18-2.99(m，2H)，1.43(s，4.5H)，1.41(s，4.5H)，1.33(d，1.5H，J＝6.75Hz)，1.21(d，1.5H，J＝6.75Hz)。

C ₂₇H ₃₁F ₂N ₃O ₅(MW=515.56); Mass spectrum (MH ⁺) 516.2.

Embodiment 5

2-[1-(3,5-difluorophenyl kharophen) ethyl]-the 4-methoxycarbonyl-

Synthesizing of 4-phenmethyl-2-tetrahydroglyoxaline

According to above universal method D, with the product of above embodiment 4, preparation title compound white solid (93%), its fusing point is 158-160 ℃.By tlc monitoring reaction (Rf=0.31 launched among the DCM/MeOH at 95: 5).

The NMR data are as follows:

¹H-nmr (DMSO-d ₆And CDCl ₃, 250MHz): δ=8.09 (bt, 1H, J=7.75Hz), 7.28-7.19 (m, 3H), 7.14-7.09 (m, 2H), 6.89 (bd, 2H, J=7.25Hz), 6.74 (bt, 1H, J=9.13Hz), 4.62-4.48 (m, 1H), 3.88 (bd, 1H, J=12.51Hz), 3.68 (s, 3H), 3.61-3.54 (m, 1H), 3.50 (s, 2H), 3.11-2.92 (m, 2H), 1.31 (d, 1.5H, J=6.75Hz), 1.30 (d, 1.5H, J=7.00Hz).

C ₂₂H ₂₀F ₂N ₃O ₃(MW=415.44); Mass spectrum (MH ⁺) 416.1.

Embodiment 6

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-5 (R, S)-

Synthesizing of ethoxycarbonyl-2-oxazoline

According to universal method A, with 3,5-difluorophenyl acetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5 (R, S)-ethoxycarbonyl-2-oxazoline (embodiment F), the preparation title compound be a semisolid.(Rf=0.3 is at 5%MeOH/CHCl by the tlc monitoring reaction ₃The middle expansion), by silica gel column chromatography, use 5%MeOH/CHCl ₃As the eluent purified product.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.20(t，3H)，1.30(d，3H)，3.50(s，2H)，3.80(m，1H)，4.05(m，1H)，4.15(q，2H)，4.55(m，1H)，5.10(m，1H)，6.97(d，2H)，7.08(m，1H)，8.60(d，1H)。

C ₁₆H ₁₈F ₂N ₂O ₄(MW=340.33); Mass spectrum (MH ⁺) 340.

Embodiment 7

2-[1-(3,5-difluorophenyl kharophen) ethyl]-the 4-methoxycarbonyl-

Synthesizing of 4-phenyl-2-tetrahydroglyoxaline

Steps A-1-tert-butyl ester base-2-[1-(3,5-difluorophenyl kharophen) ethyl]-

Synthesizing of 4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline

According to above universal method C, with 3,5-difluorophenyl acetic acid (Aldrich) and 1-tert-butyl ester base-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline (embodiment K), preparation title compound white foam (90%).By tlc monitoring reaction (Rf=0.39 launched among hexane/EtOAc at 3: 2), product is by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，250MHz)：δ＝7.38-7.31(m，5H)，7.09(d，1H，J＝7.50Hz)，6.90-6.82(m，2H)，6.76-6.66(m，1H)，5.57(p，1H，J＝7.50Hz)，4.83(d，1H，J＝11.26Hz)，3.87(d，1H，J＝11.26Hz)，3.72(s，3H)，3.56(s，2H)，1.49(s，9H)，1.48(d，3H，J＝7.00Hz)。

C ₂₆H ₂₉F ₂N ₃O ₅(MW=501.53); Mass spectrum (MH ⁺) 502.

Step B-2-[1-(3,5-difluorophenyl kharophen) ethyl]-

Synthesizing of 4-methoxycarbonyl-4-phenyl-2-tetrahydroglyoxaline

According to above universal method D, with the product of above steps A, preparation title compound white foam (89%).By tlc monitoring reaction (Rf=0.24 launched among the DCM/MeOH at 95: 5), product is by the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆，300MHz)：δ＝8.47(d，1H，J＝7.89Hz)，7.34-7.27(m，5H)，7.12-7.06(m，1H)，7.03-7.00(m，2H)，4.55(p，1H，J＝7.35Hz)，4.34(bm，1H)，3.62(s，2H)，3.53(s，2H)，1.31(d，3H，J＝7.00Hz)。

C ₂₁H ₂₁F ₂N ₃O ₃(MW=401.41); Mass spectrum (MH ⁺) 402.

Embodiment 8

1-tert-butyl ester base-2-(3,5-difluorophenyl methyl)-4-ethoxycarbonyl-

Synthesizing of 4-methyl-2-tetrahydroglyoxaline

Steps A-2,3-diamino-2 Methylpropionic acid ethyl ester synthetic

According to Gilbert etc., Tetrahedron, method described in 1,995 51, the 6315-6336, preparation title compound oily matter.By Kugelrohr distillation carrying out purifying.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝4.06(m，2H)，2.70(d，1H)，2.46(d，1H)，2.18(bs，4H)，1.18(t，3H)，1.10(s，3H)。

C ₆H ₁₄N ₂O ₂(MW=146.19); Mass spectrum (MH ⁺) 147.

Step B-2-(3,5-difluorophenyl methyl)-4-ethoxycarbonyl-

Synthesizing of 4-methyl-2-tetrahydroglyoxaline

The product and the 20ml ethanol that in being furnished with the round-bottomed flask of another feed hopper, add the above embodiment L of 2.25g (9.55mmole) steps A.Flask is cooled to 0 ℃, under nitrogen atmosphere, begins to stir.(1.40g 9.55mmole) adds in reactant by another feed hopper lentamente with the product of the above steps A in the 20ml ethanol.Allowing reactant be slowly to warm to room temperature and to stir spends the night.Then mixture is filtered concentrated filtrate on rotatory evaporator by sintered glass funnel.Resistates distributes between 50ml 1.0N sodium hydroxide and 50ml methylene dichloride.Separate organic phase, water layer 50ml washed with dichloromethane 2 times.The organic layer that merges is with the washing of 50ml saturated brine and through dried over sodium sulfate.Filter then and on rotatory evaporator, concentrate, produce yellow oil, with it by silica gel 60 (230-400 order) flash chromatography purifying, with 95: 5 DCM/MeOH as eluent.Concentrate the title compound (Rf=0.17 launched among the DCM/MeOH at 95: 5) that described component produces 2.61g (82% yield).

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝7.05(m，3H)，4.04(m，2H)，3.75(d，J＝11.71Hz，1H)，3.49(s，2H)，3.27(d，J＝11.73Hz，1H)，1.29(s，3H)，1.17(t，3H)。

C ₁₄H ₁₆F ₂N ₂O ₂(MW=282.29); Mass spectrum (MH ⁺) 282.1.

Step C-1-tert-butyl ester base-2-(3,5-difluoro phenmethyl)-4-ethoxycarbonyl-

Synthesizing of 4-methyl-2-tetrahydroglyoxaline

In having the round-bottomed flask of another feed hopper, add above step B product (2.00g, 7.08mmole), 0.743g (8.85mmole) sodium bicarbonate, 30ml water and 30ml THF.Begin to stir under nitrogen atmosphere, (3.47g, 15.90mmole) (Aldrich) adds in the reactant by adding funnel with the tert-Butyl dicarbonate among the 15ml THF.Stir after 1 hour, in the tert-Butyl dicarbonate adding reactant with another part 627mg (7.05mmole) sodium bicarbonate and 1.17g (5.40mmole).Use the thin-layer chromatography detection reaction,, reaction mixture is distributed between 250ml ethyl acetate and 250ml saturated brine when reaction is finished.Organic layer is with 250ml saturated brine washing 2 times, through dried over sodium sulfate.Filter the back and on rotatory evaporator, concentrate, produce yellow oil, by silica gel 60 (230-400 order) flash chromatography, adopt 15: 85 ethyl acetate/dichloromethane to carry out purifying it as eluent.Concentrate described component and produce 2.10g (yield 78%) title compound (Rf=0.15 launched in the ethyl acetate/hexane at 15: 85).

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝7.07(m，1H)，6.94(m，2H)，4.05(m，5H)，3.57(d，1H)，1.38(d，12H)，1.19(t，3H)。

¹³C-nmr(DMSO-d ₆)：δ＝172.116，163.599，160.348，157.624，149.352，140.855，111.511，101.584，81.677，69.950，60.758，55.442，34.855，27.423，24.203，13.581。

C ₁₉H ₂₄F ₂N ₂O ₄(MW=382.41); Mass spectrum (MH ⁺) 382.1.

Embodiment 9

2-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-

Synthesizing of 2-thiazoline

According to above universal method F, with N-(1-cyano group-1-phenmethyl)-N '-(3,5-difluoro phenylacetyl)-L-alanimamides and 2-mercaptoethylamine, the preparation title compound.(Rf=0.3 is at 5%MeOH/CHCl by the tlc detection reaction ₃The middle expansion), adopt 5%MeOH/CHCl ₃As eluent, by the silica gel column chromatography purified product.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝1.31(m，3H)，3.31(m，2H)，3.50(d，2H)，4.24(m，2H)，4.55(m，1H)，4.64(d，1H)，6.30(m，1H)，6.76(m，2H)，7.33(d，5H)，7.52(m，1H)。

C ₂₁H ₂₁F ₂N ₃O ₂S (MW=417.48); Mass spectrum (MH ⁺) 417.

Embodiment 10

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-4-ethoxycarbonyl-

Synthesizing of 2-thiazoline

According to above universal method G, with the N-(3,5-difluoro phenylacetyl) phenyl glycinonitrile and the L-ethylcysteine hydrochloride (Aldrich) that derive from above example I, preparation title compound amorphous solid.By tlc detection reaction (Rf=0.5 launched in the EtOAc/ hexane at 1: 1), adopt the 40%EtOAc/ hexane as eluent, by the silica gel column chromatography purified product.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=1.36 (t, 3H), 3.6 (m, 4H), 4.30 (m, 2H), 5.10 and 5.20 (t, 1H), 5.84 (d, 1H), 6.72 (m, 1H), 6.84 (m, 2H), 7.38 (m, 5H).

C ₂₁H ₂₀F ₂N ₂O ₃S (MW=418.47); Mass spectrum (MH ⁺) 418.

Embodiment 11

2-[(S)-1-(3,5-dichlorobenzene amido) ethyl]-(S)-the 4-methoxycarbonyl-

Synthesizing of 2-oxazolidine

According to above universal method H, preparation title compound oily matter.By tlc detection reaction (Rf=0.5 launched among hexane/EtOAc at 3: 2), adopt 3: 2 hexane/EtOAc as eluent, by preparation property tlc chromatography purification product.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝1.5(d，J＝7Hz，3H)，3.79(s，3H)，4.15-4.3(m，1H)，4.3-4.65(m，3H)，4.7-4.85(m，1H)，6.45(s，2H)，6.7(s，1H)。

¹³C-nmr(CDCl ₃)：δ＝14.2，42.08，42.15，47.9，62.9，65.3，106.67，106.72，113.0，130.7，143.3，166.3。

C ₁₃H ₁₄Cl ₂N ₂O ₃(MW=317); Mass spectrum (MH ⁺) N/A.

Embodiment 12 (S)-5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-

The 3-methyl isophthalic acid, 2,4-oxadiazole synthetic

According to above universal method A; with N-(3,5-difluoro phenylacetyl)-L-L-Ala (example II-B) and (S)-5-(1-amino-1-phenmethyl)-3-methyl isophthalic acid, 2; 4-oxadiazole hydrochloride (Embodiment C), preparation title compound solid (3: 2 diastereomer compounds).(Rf=0.6 is at 7%MeOH/CHCl by the tlc detection reaction ₃The middle expansion), adopt 7%MeOH/CHCl ₃As eluent, by the silica gel column chromatography purified product, recrystallization from 1-chlorobutane/acetonitrile then.

The NMR data are as follows:

¹H-nmr (DMSO-d ₆): δ=1.21 (d, 3H), 2.32 (s, 3H), 3.53 (s, 2H), 4.43 (m, 1H), 6.35 (d, 1H), 6.97 (d, 2H), 7.07 (m, 1H), 7.38 (wide s, 5H), 8.38 (d, 1H), 9.27 (d, 1H).

C ₂₀H ₂₀F ₂N ₄O ₃(MW=414.41); Mass spectrum (MH ⁺) 414.

Embodiment 13 (S)-5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-

3-phenyl-1,2,4-oxadiazole synthetic

According to above universal method A, with N-(3,5-difluoro phenylacetyl)-L-L-Ala (example II-B) and (S)-5-(1-amino-1-phenmethyl)-3-phenyl-1,2,4-oxadiazole hydrochloride (embodiment D), preparation title compound.(Rf=0.4 is at 5%MeOH/CHCl by the tlc detection reaction ₃The middle expansion), adopt 5%MeOH/CHCl ₃As eluent, by the silica gel column chromatography purified product.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.31(d，3H)，3.51(s，2H)，4.47(m，1H)，6.42(d，1H)，6.97(d，2H)，7.07(m，1H)，7.35-7.60(m，8H)，7.97(d，2H)，8.40(d，1H)，9.27(d，1H)。

C ₂₆H ₂₂F ₂N ₄O ₃(MW=476.49); Mass spectrum (MH ^-) 476.

Embodiment 14 (S)-5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-

3-(4-mehtoxybenzyl)-1,2,4-oxadiazole synthetic

According to above universal method A; with N-(3,5-difluoro phenylacetyl)-L-L-Ala (example II-B) and (S)-5-(1-amino-1-phenmethyl)-3-(4-mehtoxybenzyl)-1,2; 4-oxadiazole hydrochloride (embodiment E), preparation title compound (1: 2 diastereomer compound).(Rf=0.25 is at 3.5%MeOH/CHCl by the tlc detection reaction ₃The middle expansion), adopt 3.5%MeOH/CHCl ₃As eluent, by the silica gel column chromatography purified product.

The NMR data are as follows:

¹H-nmr (DMSO-d ₆): δ=1.22 (d, 3H), 3.49 (s, 2H), 3.72 (s, 3H), 3.98 (s, 2H), 4.42 (m, 1H), 6.28 (d, 1H), 6.86 (d, 2H), 6.96 (d, 2H), 7.07 (m, 1H), 7,18 (d, 2H), 7.38 (wide s, 5H), 8.36 (d, 1H), 9.18 (d, 1H).

C ₂₈H ₂₆F ₂N ₄O ₄(MW=520.54); Mass spectrum (MH ⁺) 520.

Embodiment 15

(4R)-and 4-[N-(1S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-

Synthesizing of (3.5-difluoro phenmethyl)-4-methyl-2-thiazoline

In 0 ℃, under the nitrogen atmosphere, (the 4R)-4-carboxyl-2-(3 that derives from above embodiment L in THF (20ml), 5-difluoro phenmethyl)-4-methyl-2-thiazoline (0.2509g, 1.00eq.) in, add (S)-(+)-2-phenyl glycine methyl ester hydrochloride (0.2052g, 1.10eq.) (Aldrich), I-hydroxybenzotriazole hydrate (0.1437g, 1.15eq.) (Aldrich), N, N-diisopropylethylamine (0.371ml, 2.30eq.), add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.2039g, 1.15eq.) (Aldrich) then.Remove cooling bath, allow the mixture temperature, stirred simultaneously 19 hours to room temperature.This solution dilutes with ethyl acetate, with 0.5M aqueous hydrochloric acid (2 *), dilute aqueous solution of sodium bicarbonate (1 *) and salt solution (1 *) washing; Organic phase is filtered and vacuum concentration through dried over sodium sulfate then, and resistates as the eluent purifying, produces title compound clear, colorless viscosity oily matter (0.3465g, 90%) with 2: 1 hexane/EtOAc through the rapid column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃，300MHz)：δ7.59(d，1H，J＝7.25Hz)，7.36-7.27(m，5H)，6.80-6.78(m，2H)，6.75-6.68(m，1H)，5.51(d，1H，J＝7.37Hz)，3.78(s，2H)，3.74(s，3H)，2.63(d，1H?J＝11.59Hz)，2.22(d，1H，J＝11.60Hz)，1.55(s，3H)。

Specific rotation: [α] ₂₀=65.3 (c 1.0, CHCl ₃).

C ₂₁H ₂₀F ₂N ₂O ₃S (MW=418.47); Mass spectrum (MH ⁺) 418.3.

Embodiment 16

4-[N-(S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-

Synthesizing of (3.5-difluoro phenmethyl)-2-thiazoline

According to above universal method A, with L-phenyl glycine methyl ester and 2-(3.5-difluoro the phenmethyl)-4-carboxyl-2-thiazoline that derives from above embodiment H, preparation is as the title compound of 2 isolating diastereomers.By tlc detection reaction (Rf=0.6 and 0.4 launched in the EtOAc/ hexane at 1: 1), adopt the 40%EtOAc/ hexane as eluent, by the purification by silica gel column chromatography product.

First diastereomer (amorphous solid):

The NMR data are as follows:

¹H-nmr(CDCl ₃)：3.58-3.82(m，5H)，3.94(s，2H)，5.10(t，1H)，5.57(d，1H)，6.75(m，1H)，6.90(d，2H)，7.35(m，5H)，7.84(d，1H)。

C ₁₉H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (MH ⁺) N/A.

Second diastereomer (oily matter):

The NMR data are as follows:

¹H-nmr(CDCl ₃)：3.61(d，2H)，3.75(s，3H)，3.84(s，2H)，5.13(t，1H)，5.56(d，1H)，6.72(m，1H)，6.80(d，2H)，7.33(m，5H)，7.66(d，1H)。

C ₁₉H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (MH ⁺) 404.

Embodiment 17

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino] ethyl-

3-ethyl-1,2,4-oxadiazole synthetic

According to above universal method A, with N-(3,5-difluoro phenylacetyl)-L-L-Ala (example II-B) and (S)-5-(1-aminoethyl)-3-ethyl-1,2,4-oxadiazole hydrochloride (embodiment A), preparation title compound solid, its fusing point is 181-183 ℃.(Rf=0.3 is at 7% MeOH/CHCl by the tlc detection reaction ₃The middle expansion), adopt 7% MeOH/CHCl ₃As eluent, by the purification by silica gel column chromatography product, recrystallization from 1-chlorobutane then.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.20(m，6H)，1.45(d，3H)，2.70(q，2H)，3.51(s，2H)，4.32(m，1H)，5.13(m，1H)，6.98(d，2H)，7.10(m，1H)，8.38(d，1H)，8.73(d，1H)。

Specific rotation: [α] ₂₀=+53.1 in 589nm (c 1.08, DMSO).

C ₁₇H ₂₀F ₂N ₄O ₃(MW=366.37); Mass spectrum (MH ⁺) 367.

Embodiment 18

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-(4R)-the 4-methoxycarbonyl-

Synthesizing of 2-thiazoline

According to above universal method G, with deriving from N-(3,5-difluoro phenylacetyl) the phenyl glycinonitrile of above example I and (R)-acthiol-J hydrochloride (CAS 2485-62-3), the preparation title compound.Adopt 1: 1 EtOAc/ hexane as eluent, by the silica gel column chromatography purified product, crystallization from 1-chlorobutane then.

First kind of diastereomer (R _fHigher):

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝5.08(t，1H)，5.18(t，1H)，5.47(t，1H)，5.82(m，1H)。

C ₂₀H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (M ⁺) 404.

Second kind of diastereomer (R _fLower):

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝5.12(t，1H)，5.21(t，1H)，5.47(t，1H)，5.83(m，1H)。

C ₂₀H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (M ⁺) 404.

Embodiment 19

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-(4S)-the 4-methoxycarbonyl-

Synthesizing of 2-thiazoline

According to above universal method G, with deriving from N-(3,5-difluoro phenylacetyl) the phenyl glycinonitrile of above example I and (S)-acthiol-J hydrochloride (Aldrich), the preparation title compound.Adopt 2: 3 EtOAc/ hexanes as eluent, by the silica gel column chromatography purified product, crystallization from 1-chlorobutane/hexane then.

First kind of diastereomer (R _fHigher):

The NMR data are as follows:

¹H-nmr(CD ₃OD)：3.76(s，3H)，5.20(t，1H)，5.85(s，1H)。

C ₂₀H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (M ⁺) 404.

Second kind of diastereomer (R _fLower):

The NMR data are as follows:

¹H-nmr(CD ₃OD)：δ＝3.78(s，3H)，5.22(t，1H)，5.83(s，1H)。

C ₂₀H ₁₈F ₂N ₂O ₃S (MW=404.44); Mass spectrum (M ⁺) 404.

Embodiment 20

N-[2-(3,5-difluoro phenmethyl)-4-methyl-2-tetrahydroglyoxaline-4-formamido group]-

Synthesizing of L-phenyl glycine methyl ester

Steps A-1-tert-butyl ester base-2-(3,5-difluoro phenmethyl)-4-carboxyl-

Synthesizing of 4-methyl-2-tetrahydroglyoxaline

Adding 150ml THF, 50ml 0.1N lithium hydroxide aqueous solution and 1-tert-butyl ester base-2-(3,5-difluoro phenmethyl)-4-ethoxycarbonyl-4-methyl-2-tetrahydroglyoxaline (embodiment 8 step C) in the round-bottomed flask that has the mechanical stirring rod (2.58g, 6.75mmole).Reaction mixture was stirred 1 hour, add another part 75ml 0.1N lithium hydroxide aqueous solution then, continue to stir 3.5 hours.Vacuum concentration reaction mixture then, the resistates of generation distributes between ethyl acetate and 0.5N aqueous hydrochloric acid.Separate organic phase, wash with another part 0.5N aqueous hydrochloric acid.Organic phase is through dried over sodium sulfate then.Filter and remove siccative, vacuum section concentrated filtrate.The solid that produces is by the sintered glass funnel vacuum filtration, then in 80 ℃ of vacuum-dryings.

Mass-spectrometric data is as follows:

C ₁₇H ₂₀N ₂O ₄(MW=354.36); Mass spectrum (MH ⁺) 255.2.

Step B-N-[1-tert-butyl ester base-2-(3,5-difluoro phenmethyl)-4-methyl-

2-tetrahydroglyoxaline-4-formamido group]-L-phenyl glycine methyl ester synthetic

According to above universal method A, with (S)-(+)-2-phenyl glycine methyl ester hydrochloride and steps A product, the preparation title compound.By quick silica gel column chromatography (230-400 order), adopt 95: 5DCM/MeOH carries out purifying as eluent.

First kind of diastereomer (viscosity oily matter):

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.60(bs，1H)，7.35(s，5H)，6.90(m，2H)，6.69(m，1H)，5.49(d，1H)4.12(m，3H)，3.72(s，3H)，3.61(d，1H)，1.46(s，9H)，1.41(s，3H)。

Second kind of diastereomer (viscosity oily matter):

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝7.55(bs，1H)，7.31(m，5H)，6.84(m，2H)，6.67(m，1H)，5.49(d，1H)，4.08(m，3H)，3.72(s，3H)，3.56(m，1H)，1.50(s，1H)，1.43(s，9H)。

Step C-N-[2-(3,5-difluoro phenmethyl)-4-methyl-2-tetrahydroglyoxaline

-4-formamido group]-L-phenyl glycine methyl ester synthetic

According to above universal method D, with the single isomer of step B, preparation is as the title compound of 2 separating isomerism bodies.By quick silica gel column chromatography (230-400 order), adopt 97.5: 2.5DCM/MeOH carries out purifying as eluent.

First kind of diastereomer:

Mass-spectrometric data is as follows:

C ₂₁H ₂₁F ₂N ₂O ₃S (MW=401.42); Mass spectrum (MH ^-) 402.0.

Second kind of diastereomer:

Mass-spectrometric data is as follows:

C ₂₁H ₂₁F ₂N ₂O ₃S (MW=401.42); Mass spectrum (MH ^-) 402.0.

In addition, following universal method and embodiment provide the various carboxylic acids (with adopting following universal method AC or BD hydrolysis to obtain the carboxylicesters of corresponding carboxylic acid) that can be used for preparing other compound in the scope of the invention.

Universal method AA

Reduction amination

Add 1 normal 2-oxo carboxylic acid ester (for example pyruvate) in the ethanolic soln of the arylamines in the hydrogenation flask, add 10% palladium carbon (based on 25% (weight) of described arylamines) then.On Parr jolting device,, finish (30 minutes to 16 hours) until tlc demonstration reaction with reactant hydrogenation under 20psi hydrogen.Making reaction mixture pass through diatomite 545 pads then (derives from Aldrich Chemical Company, Inc.) filters, get on to desolventize at rotatory evaporator.Then the crude product resistates is further purified by chromatography.

Universal method AB

First kind of transesterification method

The normal required alcoholic solution of 1-5 is added in the toluene solution of 1 sodium hydride of working as.After stopping the degassing, add the compound for the treatment of transesterification that is dissolved in the toluene.0.5 after hour, with reactant be heated to 40 ℃ and place vacuum (～20mmHg) under, or nitrogen fed in this solution, simultaneously with it in 90 ℃ of heating.Carry out tlc after the reaction, when reaction is finished, cool off this solution, water or 1M HCl quencher, and a spot of reactant diluted with ethyl acetate.Organic phase extracts with saturated sodium bicarbonate aqueous solution, uses saturated NaCl solution washing then and through dried over mgso.Get on to desolventize at rotatory evaporator, the crude product resistates is further purified through chromatography then.Perhaps, by evaporating solvent and directly carry out the chromatography of crude mixture, reaction mixture.

This method is particularly useful under the situation of costliness and/or high-boiling point alcohol.

Universal method AC

Second kind of transesterification method

The compound for the treatment of transesterification is placed a large amount of excessive required alcohol.Add the anhydrous Na H of catalytic amount, carry out tlc after the reaction, until the existence that no longer detects raw material.Reactant is with several milliliters of 1N HCl quencher, after the stirred for several minute, adds saturated sodium bicarbonate aqueous solution.Organic phase is with saturated NaCl solution washing and through dried over mgso.Get on to desolventize at rotatory evaporator, the crude product resistates is further purified through chromatography then.

Universal method AD

The third transesterification method

The compound for the treatment of transesterification is placed a large amount of excessive required alcohol.Add the anhydrous Na H of catalytic amount, carry out tlc after the reaction, until the existence that no longer detects raw material.Reactant is with several milliliters of 1N HCl quencher, after the stirred for several minute, adds saturated sodium bicarbonate aqueous solution.On rotatory evaporator, reduce the volume of reaction mixture,, then remaining resistates is absorbed in the ethyl acetate, add other water until removing excessive alcohol.Organic phase is with saturated NaCl solution washing and through dried over mgso.Get on to desolventize at rotatory evaporator, the crude product resistates is further purified through chromatography then.

This method lower boiling, cheap, can not with the situation of the miscible alcohol of water under particularly useful.

Universal method AE

The O-alkylation techniques

Add 1.5 equivalent salt of wormwood in the carboxylic acid cpd in DMF (for example carrying out reduction amination by universal method AA provides N-arylamino acid esters, then by method AF hydrolysis preparation), add 1 equivalent alkylating agent (for example bromo-acetic acid tert-butyl) then.Reactant was stirred under room temperature 2 hours, and water quencher then is extracted into it in ethyl acetate.Organic phase is with saturated sodium bicarbonate aqueous solution, water and saturated NaCl solution washing, then through dried over mgso.Get on to desolventize at rotatory evaporator, produce the crude product product.

Universal method AF

Ester is hydrolyzed to free acid

Add 2-5 equivalent salt of wormwood in the carboxylic acid cpd in 1: 1 methanol/water mixture (for example carrying out reduction amination by universal method AA provides N-arylamino acid esters to prepare).With mixture heating up to 50 ℃ 0.5-1.5 hour, finish until tlc demonstration reaction.Reactant is cooled to room temperature, on rotatory evaporator, removes methyl alcohol.The pH of remainder water solution is transferred to～2, add the ethyl acetate extraction product.Organic phase is with saturated NaCl solution washing, and through dried over mgso.Get on to desolventize at rotatory evaporator, produce the crude product product.

Universal method AG

The N-heteroarylization of L-Ala

The DMSO solution of 1.1 normal L-L-Ala and 2 normal NaOH was stirred under room temperature 1 hour, add 1 equivalent 2-chloro benzothiazole then.With mixture heating up to 100 ℃ 4 hours, be cooled to room temperature then, and inject on ice.The pH of the aqueous solution that produces is transferred to～2, filter and take out precipitated solid.This solid is dissolved among the A 1N NaOH, and the solution of generation filters by diatomite 545 pads.The pH of filtrate is transferred to～2, filter and take out white precipitate, wash with water, produce the crude product product.

Universal method AH

The EDC coupling

In the dichloromethane solution of 0 ℃ of 1: 1 required acid and alcohol, add 1.5 equivalent triethylamines, add 2.0 equivalent hydroxybenzotriazole monohydrates then, add 1.25 equivalent ethyl-3-(3-dimethylamino)-propyl carbodiimide diimmonium salt hydrochlorate (EDC) then.Reactant stirred under room temperature spend the night, be transferred to then in the separating funnel, water, saturated sodium bicarbonate aqueous solution, 1N HCl and saturated NaCl solution washing are then through dried over mgso.Get on to desolventize at rotatory evaporator, produce the crude product product.

Universal method AI

Oxime or amine coupling technology

The trichlorophenyl ester (1eq.) of carboxylic acid is stirred in DMF or THF.Add oxime or amine (1.2eq.), mixture was stirred under room temperature 1-4 hour.Under the situation of the hydrochloride form that uses amine, also add suitable alkali, such as N, N-diisopropylethylamine (1.2eq.).The mixture that concentrating under reduced pressure produces produces the crude product product, and it is purified and use, or through silica gel column chromatography and/or crystallization purifying.

Universal method AJ

Alkylation techniques

Described amine (1eq.), described alpha-brominated ester (1.1eq.) and suitable alkali (such as triethylamine) (2eq.) are stirred in chloroform.With the solution reflux that produces 4-12 hour.After the cooling, mixture dilutes with chloroform and washes with water.With organic moiety drying (sodium sulfate), and concentrating under reduced pressure.The crude product product is through the silica gel column chromatography purifying.

Universal method AK

Oxime or pure coupling technology

Carboxylic acid (1eq.) is stirred in suitable solvent (such as THF, diox or DMF).Add alcohol or oxime (1-5eq).Add EDC hydrochloride (1.2eq.) and hydroxy benzotriazole hydrate (1eq.).Add suitable alkali (such as 4-methylmorpholine or triethylamine) (0-1q).The 4-dimethylaminopyridine that adds catalytic amount (0.1eq).Mixture stirs down in room temperature, nitrogen atmosphere.After 20 hours, the concentrating under reduced pressure mixture.The concentrated solution that produces distributes between ethyl acetate and water.Separate organic moiety, with sodium bicarbonate aqueous solution and salt water washing.With organic moiety drying (sodium sulfate) and concentrating under reduced pressure.The crude product product is purified and use or through silica gel column chromatography and/or crystallization purifying.

Universal method AL

The EDC coupling

Described carboxylic acid is dissolved in the methylene dichloride.Order adds described amino acid (1eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2eq.).Apply cooling bath to round-bottomed flask, reach 0 ℃ until solution.At this moment, add 1.2eq.1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC).Solution stirring is spent the night, and be issued to room temperature at nitrogen pressure.By with saturated aqueous sodium carbonate, 0.1M citric acid and salt water washing organic phase, use dried over sodium sulfate then, reaction mixture.Remove then and desolvate, produce crude product.In suitable solvent, obtain pure products through flash chromatography.

Universal method AM

The trifluoroacetic acid ester interchange

In the dichloromethane solution of 0 ℃ (R)-(+)-lactic acid tert-butyl ester, add 1.1 normal trifluoromethanesulfanhydride anhydrides.After stirring 20 minutes under the room temperature, add 1.1 normally 2, the 6-lutidine continues to stir 10 minutes.Then this solution is transferred in the flask, this flask contains described arylamines of 1 equivalent and 1 equivalent N, the methylene dichloride of N-diisopropylethylamine or CH ₃NO ₂0 ℃ of solution.Reactant is kept spending the night under room temperature, on rotatory evaporator, remove then and desolvate.Resistates is dissolved in the ethyl acetate,,,, on rotatory evaporator, removes then and desolvate, produce crude product through sal epsom or dried over sodium sulfate then with the saturated sodium-chloride water solution washing with 5% citric acid washing, then with it through chromatography purification.

Universal method AN

The removal of BOC

The compound of BOC protection is added in 1: 1 mixture of methylene dichloride and trifluoroacetic acid, stir until tlc demonstration conversion and finish, be generally 2 hours.Evaporating solns is absorbed into resistates in the ethyl acetate, and extracts with dilute hydrochloric acid to doing then.In and acid reactant, and use ethyl acetate extraction.Organic phase is with the saturated sodium-chloride water solution washing and through dried over mgso.On rotatory evaporator, remove the solvent in the solution, produce described product.

Universal method AO

Synthesizing of pyruvate

To pyruvic acid (8.8g, 0.1mol) add in the mixture of the 100ml benzene of (Aldrich) isopropylcarbinol (14.82g, 0.2mol) and the tosic acid of catalytic amount.With Dean Stark device mixture is refluxed then.As if after 4 hours, this reaction is finished, isolate 1.8g (0.1mol) water.On rotatory evaporator, remove benzene and isopropylcarbinol.(14g 0.1mol) is mainly pyruvic acid isobutyl ester, nmr[to described resistates ¹H-Nmr (CDCl ₃): δ=4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m, 1H), 1.0 (d, 6H)].By replacing isopropylcarbinol (for example ethanol, Virahol, propyl carbinol, phenylcarbinol etc.), can prepare other pyruvate in a similar manner with other alcohol.

Universal method AP

The aromatics nucleophilic substitution of fluorobenzene

With the D of 1.82g (10mmol), the 10ml DMSO mixture of L-L-Ala isobutyl ester hydrochloride, described fluorobenzene (10mmol) and 3g Anhydrous potassium carbonate stirred 2-5 hour in 120 ℃.Then, reaction mixture is cooled to room temperature, and dilutes with the 100ml ethyl acetate.Acetic acid ethyl ester extract water (3 *) washing through dried over mgso, and is evaporated to driedly, obtains described crude product, and it is further purified through column chromatography.

Universal method AQ

The 4th kind of transesterification technology

The ester for the treatment of transesterification is dissolved in a large amount of excessive described alcohol, adds 0.3 normal titanium isopropylate (IV) (Aldrich).Follow the tracks of reaction to reaction with tLc and finish, volatile matter is removed in decompression then.Then, the crude product material of generation obtains required product through chromatography.

Universal method AR

Synthesizing of N-BOC aniline

In the THF of described aniline solution, drip the THF solution of 1 equivalent tert-Butyl dicarbonate (Aldrich), add 1.5 equivalent 10N sodium hydroxide water liquid in 0 ℃ then.In stirring under the room temperature 16 hours or after 3 hours, if desired, reaction mixture diluted with ether in 80 ℃ of heating, and with sodium bicarbonate, salt water washing, and through sodium sulfate and salt of wormwood drying, concentrating under reduced pressure and chromatographic separation obtain N-BOC aniline.

Universal method AS

The generation of oxime ester

(1eq.) stirs in DMF or THF with the trichlorophenyl ester.Add described oxime (1.2eq.), mixture was stirred under room temperature 1-4 hour.The mixture that concentrating under reduced pressure produces, resistates is through silica gel column chromatography and/or crystallization purifying.

Embodiment A A

D, L-L-Ala isobutyl ester hydrochloride synthetic

With the D of 35.64g (0.4mol), the mixture of L-L-Ala (Aldrich), 44ml (0.6mol) thionyl chloride (Aldrich) and 200ml isopropylcarbinol refluxed 1.5 hours.Remove volatile matter in 90 ℃ of decompressions, obtain title compound oily matter, it is used without being further purified.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.72(br?s，3H)，4.27(q，J＝7.4Hz，1H)，3.95(m，2H)，1.96(s，1H)，1.73(d，J＝7.2Hz，3H)，0.92(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝170.0，72.2.，49.2，27.5，18.9，16.1。

Embodiment A B

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala

Adopt the method for the 3rd, 598, No. 859 (whole by reference being attached to herein) propositions of United States Patent (USP), preparation N-(3, the 4-chloro-phenyl-) L-Ala.Specifically, to 3, add entry (the about 0.06ml of every ml Virahol) in 4-dichlorphenamide bulk powder (1 equivalent) Virahol (every mole 3, the about 500ml of the 4-dichlorphenamide bulk powder) solution (Aldrich) and 2-chloropropionic acid (2 equivalent) (Aldrich).With mixture temperature to 40 ℃, add sodium bicarbonate (0.25 equivalent) continuously, reflux 4-5 days then.After the cooling, in reaction mixture impouring water, remove by filter unreacted 3, the 4-dichlorphenamide bulk powder.With concentrated hydrochloric acid filtrate is acidified to pH3-4, filters the precipitation that produces, washing is also dry, produces title compound, m.p.=148-149 ℃.

Perhaps,, adopt N-(3, the 4-dichlorophenyl) alanine ethyl esters (from following examples A1), the preparation title compound according to above universal method AF.

Embodiment A C

Synthesizing of N-(3, the 5-difluorophenyl) L-Ala

The method that adopts United States Patent (USP) to propose for the 3rd, 598, No. 859, with 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich) preparation N-(3, the 5-difluorophenyl) L-Ala.

Embodiment A D

Synthesizing of 2 bromopropionic acid isobutyl ester

In the anhydrous diethyl ether mixture of isopropylcarbinol and 1.0 equivalent pyridines, drip 1.3 equivalent 2 bromo propionyl bromides in 0 ℃.After stirring 16 hours under the room temperature, reactant dilutes with ether, with 1NHCl, water, sodium bicarbonate aqueous solution, salt water washing, and through sal epsom or dried over sodium sulfate.Removal of solvent under reduced pressure produces the transparent oily matter of title compound.

Embodiment A E

N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester synthetic

(5.0g 20.6mmol) (derives from following examples A44) and is dissolved in the diox (100ml) with N-(2-naphthyl) alanine methyl ester.Add sodium hydroxide (30ml, 1N), with the solution stirring that produces 1 hour.The concentrating under reduced pressure reaction mixture.The solid that produces is soluble in water, wash aqueous mixture with ether.Water-based partly is adjusted to pH3 and uses ethyl acetate extraction with 1N HCl.Organic extract is through sal epsom or sodium sulfate is dry and concentrating under reduced pressure, produces white solid (4.35g, 98%).

(4.35g 20mmol) is dissolved in the methylene dichloride (300ml) with the solid that produces.Add 2,4, (4.9g, 25mmol) (Aldrich) add dicyclohexyl carbodiimide (25ml, 1M dichloromethane solution) (Aldrich) to the 5-Trichlorophenol then.Stir after 18 hours, filter and enriched mixture, obtain oily matter, through the silica gel column chromatography purifying, adopt chloroform it as eluent (R _f=0.6).Obtain the thick oily matter of slow crystalline title compound.

Embodiment A 1

Synthesizing of N-(3, the 4-dichlorophenyl) alanine ethyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.4 launches in 25% EtOAc/ hexane), through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)；6.7(d，1H)；6.4(dd，1H)；4.30(bs，1H)；4.2(q，2H)；4.1(q，1H)：1.5(d，3H)；1.3(t，3H)。

¹³C-nmr(CDCl ₃)：δ＝175；146.7；133；131；121；114.9；112.6；72.0；52.4；28.3；19.5。

C ₁₁H ₁₃Cl ₂NO ₂(MW＝262.14)。

Embodiment A 2

Synthesizing of N-(3-trifluoromethyl-4-chloro-phenyl-) alanine ethyl ester

According to above universal method AA, with 4-chloro-3-(trifluoromethyl) aniline (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich), the preparation title compound.

Analytical calculation value: C, 48.74; H, 4.43; N, 4.74.Measured value: C, 48.48; H, 4.54; N, 4.94.

C ₁₂H ₁₃F ₃ClNO ₂(MW=295.69); Mass spectrum (MH ⁺) 295.

Embodiment A 3

Synthesizing of N-(3, the 5-dichlorophenyl) alanine ethyl ester

According to above universal method AA, with 3,5-dichlorphenamide bulk powder (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich), preparation title compound.

Analytical calculation value: C, 50.40; H, 5.00; N, 5.34.Measured value: C, 50.50; H, 5.06; N, 5.25.

C ₁₁H ₁₃Cl ₂NO ₂(MW=262.14); Mass spectrum (MH ⁺) NA.

Embodiment A 4

Synthesizing of N-(3, the 4-difluorophenyl) alanine ethyl ester

According to above universal method AA, with 3,4-difluoroaniline (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich), preparation title compound.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in the 25%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.4(m，1H)，6.8(d，1H)，6.5(m，1H)，4.30(bs，1H)，4.2(q，2H)，4.1(q，1H)，1.5(d，3H)，1.3(t，3H)。

¹³C-nmr(CDCl ₃)：δ＝175，146.7，135，132，125，116，113，72，52，28，19。

C ₁₁H ₁₃F ₂NO ₂(MW=229.23); Mass spectrum (MH ⁺) 230.

Embodiment A 5

Synthesizing of N-(3, the 4-dichlorophenyl) alanine benzyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and acetone acid benzyl ester (, replace isopropylcarbinol with benzylalcohol and be prepared), preparation title compound oily matter according to above universal method AO.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H)，7.0(m，5H)，6.6(d，1H)，6.4(dd，1H)，5.1(s，2H)，4.30(bs，1H)，4.08(q，1H)，1.94(m，1H)，1.47(d，3H)，0.91(d，6H)。

¹³C-nmr(CDCl ₃)：δ＝174.5；146.7；133.5；131.3；121.3；120.1；114.9；113.6；72.0；60.1；52.4；28.3；19.5；19.3。

C ₁₆H ₁₅Cl ₂NO ₂(MW=324.31); Mass spectrum (MH ⁺) 325.

Embodiment A 6

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala isobutyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.55 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with the 25%EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H，J＝8.7Hz)，6.66(d，1H，j＝2.7Hz)，6.43(dd，1H，J＝8.7Hz，J＝2.7Hz)，4.30(bs，1H)，4.08(q，1H，J＝6.9Hz)，1.94(sept，1H，J＝6.7Hz)，1.47(d，3H，J＝6.9Hz)，0.91(d，6H，J＝6.6Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.5，146.7，133.5，131.3，121.3，114.9，113.6，72.0，52.4，28.3，19.5，19.3。

C ₁₃H ₁₇Cl ₂NO ₂(MW=290.19); Mass spectrum (MH ^-) 290.

Embodiment A 7

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala isopropyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and pyruvic acid isopropyl ester (, replace isopropylcarbinol with Virahol and be prepared), preparation title compound oily matter according to above universal method AO.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H)，6.66(d，1h)，6.43(dd，1h)，4.30(bs，1H)，4.08(m，1H)，1.94(m，1H)，1.47(d，3H)，0.91(d，6H)。

¹³C-nmr(CDCl ₃)：δ＝174.5；146.7；133.5；131.3；121.3；114.9；113.6；72.0；52.4；19.5。

C ₁₂H ₁₅Cl ₂NO ₂(MW=276.16); Mass spectrum (MH ^-) 277.

Embodiment A 8

Synthesizing of N-(3, the 4-dichlorophenyl) the positive butyl ester of L-Ala

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and the positive butyl ester of pyruvic acid (, replace isopropylcarbinol with propyl carbinol and be prepared), preparation title compound according to above universal method AO.By silica gel tlc monitoring reaction (Rf=0.7 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H)，6.66(d，1H)，6.43(dd，1H)，4.30(bs，1H)，4.2(m，2H)，4.08(q，1H)，1.94(m，1H)，1.47(m，4H)，0.91(t，3H)。

¹³C-nmr(CDCl ₃)：δ＝174.5；146.7；133.5；131.3；121.3；114.9；113.6；72.0；52.4；28.3；20.2；19.5。

C ₁₃H ₁₇Cl ₂NO ₂(MW=290.19); Mass spectrum (MH ⁺) 291.

Embodiment A 9

Synthesizing of N-(3, the 4-dichlorophenyl) alanine methyl ester (R, S isomer)

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and Pyruvic Acid Methyl ester (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.55 launches), carry out purifying through flash chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，J＝8.73Hz，1H)，6.66(d，J＝2.75Hz，1H)，6.43(dd，J＝8.73Hz，2.80Hz，1H)，4.25(bd，J＝8.25Hz，1H)，4.08(m，1H)，3.76(s，3H)，1.47(d，J＝6.90Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.35，145.96.132.87，130.70，120.76，114.38，112.90，52.43，51.70，18.67。

C ₁₀H ₁₁C _L2NO ₂(MW=248.11); Mass spectrum (MH ⁺) 247.

Embodiment A 10

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala ring pentyl ester

According to above universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and cyclopentanol (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.66 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H，J＝8.7Hz)，6.66(d，1H，J＝2.7Hz)，6.43(dd，1H，J＝8.7Hz，2.7Hz)，5.22(m，1H)，4.27(d，1H，J＝8.1Hz)，4.02(quint，1H，J＝7.5Hz)，1.74(m，8H)，1.43(d，3H，J＝6.9Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.3，146.7，133.4，131.2，121.2，114.9，113.7，78.9，52.5，33.2，24.2，24.1，19.1。

C ₁₄H ₁₇Cl ₂NO ₂(MW=302.20); Mass spectrum (MH ⁺) 301.

Embodiment A 11

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala n-propyl

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and pyruvic acid n-propyl (, replacing isopropylcarbinol to be prepared), preparation title compound oily matter with n-propyl alcohol according to universal method AO.By silica gel tlc monitoring reaction (Rf=0.5 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)，6.6(d，1H)，6.4(dd，1H)，4.30(bs，1H)，4.2(q，2H)，4.08(q，1H)，1.94(m，2H)，1.5(d，3H)，0.95(t，3H)。

¹³C-nmr(CDCl ₃)：δ＝178；144.7；130.2；120.62；115.11；71.82；52.90。

C ₁₂H ₁₅Cl ₂NO ₂(MW=276.16); Mass spectrum (MH ⁺) 277.

Embodiment A 12

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala allyl ester

According to above transesterification universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and allyl ester (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.62 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H，J＝8.7Hz)，6.67(d，1H，J＝2.8Hz)，6.44(dd，1H，J＝8.7Hz，J＝2.8Hz)，5.90(m，1H)，5.30(m，2H)，4.64(m，2H)，4.26(m，1H)，4.10(m，1H)，1.48(d，3H，J＝6.9Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.1，146.6，133.5，132.1，131.3，121.4，119.6，115.0，113.6，66.5，52.4，19.3。

C ₁₂H ₁₃Cl ₂NO ₂(MW=274.15); Mass spectrum (MH ⁺) 273.

Embodiment A 13

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala 4-methyl pentyl ester

According to above transesterification universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and 4-methyl amyl alcohol (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.70 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H，J＝8.7Hz)，6.66(d，1H，J＝2.7Hz)，6.43(dd，1H，J＝8.7Hz，J＝2.7Hz)，4.28(m，1H)，4.10(m?3H)，1.55(m，6H)，1.19(m，2H)，0.87(d，3H，J＝6.6Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.6，146.7，133.4，131.3，121.3，115.0，113.6，66.4，52.4，35.4，28.2，27.0，23.0，19.3。

C ₁₅H ₂₁Cl ₂NO ₂(MW=318.25); Mass spectrum (MH ⁺) 317.

Embodiment A 14 N-(3, the 4-dichlorophenyl) L-Ala 2,2-dimethyl-1,3-dioxolane-4-methyl esters synthetic

According to above transesterification universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and 2,2-dimethyl-1,3-dioxolane-4-methyl alcohol (solketal) (Aldrich) prepares the title compound as non-enantiomer mixture.By silica gel tlc monitoring reaction (Rf=0.32 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H，J＝8.7Hz)，6.66(d，1H，2.7Hz)，6.43(dd，1H，J＝8.7Hz，J＝2.7Hz)，4.22(m，6H)，3.70(m，1H)，1.43(m，9H)。

¹³C-nmr(CDCl ₃)：δ＝174.34，174.32，146.5，133.5，131.3，121.5，115.0，113.6，110.52，110.51，73.97，73.89，66.6，66.01，65.95，52.42，52.37，27.3，25.8，19.3。

C ₁₅H ₁₉Cl ₂NO ₄(MW=348.23); Mass spectrum (MH ⁺) 347.

Embodiment A 15

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala cyclohexyl methyl esters

According to above transesterification universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and hexahydrobenzyl alcohol (Aldrich), the preparation title compound.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H)，6.68(d，1H)，6.45(dd，1H)，4.26(bd，1H)，4.10(m，1H)，3.95(d，2H)，1.70-1.55(m，6H)，1.50(d，3H)，1.35-0.85(m，5H)。

¹³C-nmr(CDCl ₃)：δ＝174.58，146.72，133.48，131.27，121.34，114.98，113.72，71.06，52.52，37.68，30.10，26.83，26.17，19.32。

C ₁₅H ₂₁Cl ₂NO ₂(MW=318.250); Mass spectrum (MH ⁺) 317.

Embodiment A 16

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala tert-butyl ester base methyl esters

According to above universal method AE, with N-(3, the 4-dichlorophenyl) L-Ala (deriving from above embodiment A B) and bromo-acetic acid tert-butyl (Aldrich), preparation title compound solid.By silica gel tlc monitoring reaction (Rf=0.57 launches in 25% EtOAc/ hexane).Carry out purifying through recrystallization from ethanol.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H)，6.68(d，1H)，6.45(dd，1H)，4.55(m，2H)，4.20(m，2H)，1.55(d，3H)，1.45(s，9H)。

¹³C-nmr(CDCl ₃)：δ＝173.9，166.9，146.5，133.5，131.3，115.1，113.6，83.4，62.2，52.2，28.6，19.3。

C ₁₅H ₁₉Cl ₂NO ₂(MW=348.23); Mass spectrum (MH ⁺) 347.

Embodiment A 17

Synthesizing of N-(3, the 4-dichlorophenyl) the leucine tert-butyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and 4-methyl-2-oxopentanoic acid isobutyl ester (, being prepared), preparation title compound oily matter with 4-methyl alcohol-2-oxopentanoic acid (Fluka) and isopropylcarbinol according to universal method AO.By silica gel tlc monitoring reaction (Rf=0.6 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)，6.5(d，1H)，6.4(dd，1H)，4.30(bs，1H)，4.08(q，1H)，3.8(m，2H)，1.8(m，3H)，0.91(m，12H)。

¹³C-nmr(CDCl ₃)：δ＝174.5，146.7，133.5，131.3，121.3，114.9，113.6，72.0，52，28.3，20.1，19.5。

C ₁₆H ₂₃Cl ₂NO ₂(MW=332.27); Mass spectrum (MH ⁺) 333.

Embodiment A 18

2-[N-(3, the 4-dichlorophenyl) amino] isobutyl isovalerate synthetic

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and 2-oxopentanoic acid isobutyl ester (, being prepared), preparation title compound oily matter with 2-oxopentanoic acid (Fluka) and isopropylcarbinol according to universal method AO.By silica gel tlc monitoring reaction (Rf=0.5 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in the 25%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)，6.6(d，1H)，6.4(dd，1H)，4.3(d，1H)，3.8(m，3H)，1.9(m，6H)，1.0(t，3H)，0.9(m，6H)。

¹³C-nmr(CDCl ₃)：δ＝178；144.7；130.2；120.62；115.11；71.82；52.90；28.30；19.53。

C ₁₅H ₂₁Cl ₂NO ₂(MW=318.3); Mass spectrum (MH ⁺) 319.

Embodiment A 19

Synthesizing of N-(4-cyano-phenyl) L-Ala isobutyl ester

According to above universal method AP, with 4-fluorine benzonitrile (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above embodiment A A), preparation title compound oily matter.Reclaim product by silica gel column chromatography, with 1: 5 EtOAc/ hexane as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.44(d，J＝8.8Hz，2H)，6.57(d，J＝8.8Hz，2H)，4.74(d，J＝8.1Hz，1H)，4.18(t，J＝7.4Hz，1H)，3.95(m，2H)，1.94(m，1H)，1.51(d，J＝6.9Hz，3H)，0.91(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.4，149.7，133.8，120.1，112.7，99.8，71.6，51.2，27.7，18.9，18.6。

C ₁₄H ₁₈N ₂O ₂(MW=246.31); Mass spectrum (MH ⁺) 247.

Embodiment A 20

Synthesizing of N-(3-chloro-4-cyano-phenyl) L-Ala isobutyl ester

According to above universal method AP, with 2-chlorine 4-fluorine benzonitrile (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above embodiment A A), preparation title compound.Reclaim product by silica gel column chromatography, with 1: 5 EtOAc/ hexane as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.40(d，J＝8.5Hz，1H)，6.62(d，J＝2.3Hz，1H)，6.48(d，J＝2.4，8.6Hz，1H)，4.90(d，J＝7.6Hz，1H)，4.16(quinet，J＝7.1Hz，1H)，3.96(dd，J＝2.2，6.7Hz，2H)，1.97(m，1H)，1.51(d，J＝7.0Hz，3H)，0.93(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.0，150.4，138.3，134.9，117.3，112.8，111.3，100.6，71.7，51.1，27.7，18.9，18.4。

C ₁₄H ₁₇N ₂O ₂Cl (MW=280.76); Mass spectrum (MH ⁺) 281.

Embodiment A 21

Synthesizing of N-(3,4-dichloro-phenyl) L-Ala isobutyl ester (S isomer)

According to above universal method AM, with 3,4-dichlorphenamide bulk powder (Aldrich) and R-(+)-isobutyl lactate (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.55 launches in the 25%EtOAc/ hexane).Through column chromatography purification.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.19 (d, J=8.73,1H), 6.67 (d, J=2.75,1H), 6.45 (dd, J=8.73, J=2.75,1H), 4.28 (bd, J=8.36,1H), 4.09 (quint, 1H), 3.94 (native J=6.66,2H), 1.95 (septets, J=6.71,1H), 1.49 (d, J=6.90,3H), 0.92 (d, J=6.04,6H).

¹³C-nmr(CDCl ₃)：δ＝174.57，146.67，133.47，131.28，121.29，114.93，113.63，71.01，52.43，28.30，19.55，19.33。

C ₁₃H ₁₇Cl ₂NO ₂(MW=290.1 9); Mass spectrum (MH ⁺) 290.

Embodiment A 22

Synthesizing of N-(3, the 4-dichloro) L-Ala tetrahydrofuran (THF)-3-base-methyl esters

According to above transesterification universal method AB, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and tetrahydrofuran (THF)-3-furfuralcohol (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.33 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with the 25%EtOAc/ hexane as eluent) in the 25%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，1H，J＝8.7?Hz)，6.65(d，1H)，J＝2.7?Hz)，6.42(dd，1H，J＝8.7?Hz，J＝2.7?Hz)，4.30(m，1H)，4.09(m，3H)，3.78(m，3H)，3.53(m，1H)，2.56(m，1H)，1.94(m，1H)，1.58(m，1H)，1.46(d，3H，J＝6.9Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.5，146.6，133.5，131.3，121.4，114.9，113.6，70.86，70.83，68.2，67.31，67.29，52.4，38.7，29.36，29.33，19.2。

C ₁₄H ₁₇Cl ₂NO ₃(MW=318.20); Mass spectrum (MH ⁺) 318.

Embodiment A 23

Synthesizing of N-(3, the 5-dichlorophenyl) L-Ala n-propyl

According to above universal method AA, with 3,5-dichlorphenamide bulk powder (Aldrich) and pyruvic acid n-propyl (can substitute isopropylcarbinol with n-propyl alcohol and be prepared), preparation title compound according to universal method AO.

Embodiment A 24

2-[N-(3, the 4-dichlorophenyl) amino] isobutyl butyrate synthetic

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and 2-ketobutyric acid isobutyl ester (according to above universal method AO, with 2-ketobutyric acid (Aldrich) and isopropylcarbinol preparation), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in the 25%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)，6.6(d，1H)，6.4(dd，1H)，4.3(d，1H)，3.8(m，3H)，1.9(m，3H)，1.0(t，3H)，0.9(m，6H)。

¹³C-nmr(CDCl ₃)：δ＝178；144.7；130.2；120.62；115.11；71.82；52.90；28.30；20.5；19.53。

C ₁₄H ₁₉Cl ₂NO ₂(MW=304.22); Mass spectrum (MH ⁺) 305.

Embodiment A 25

Synthesizing of N-(4-chloro-phenyl-) L-Ala isobutyl ester

According to above universal method AA, with 4-chloroaniline (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.6 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.18 (d, 2H), 6.66 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (septet, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

C ₁₃H ₁₈ClNO ₂(MW=255.75); Mass spectrum (MH ⁺) 256.

Embodiment A 26

Synthesizing of N-(3, the 5-dichlorophenyl) L-Ala isobutyl ester

According to above universal method AA, with 3,5-dichlorphenamide bulk powder (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(d，2H)，6.66(m，1H)，4.30(bs，1H)，4.08(q，1H)，1.94(m，1H)，1.47(d，3H)，0.91(d，6H)。

C ₁₃H ₁₇Cl ₂NO ₂(MW=290.2); Mass spectrum (MH ⁺) 291.

Embodiment A 27

Synthesizing of N-(4-ethylphenyl) alanine methyl ester

In the presence of 10% palladium carbon of catalytic amount, with the hydrogenation 16 hours under 30-15psi hydrogen of the ethanolic soln of 0.68g (5mmol) 4 '-glycyl benzophenone (Aldrich), 0.60ml 90% Pyruvic Acid Methyl ester (Aldrich) and 0.05g (0.25mmol) tosic acid.Reaction mixture by diatomite filtration, is removed catalyzer, and evaporating solvent obtains crude product.This product obtains title compound through column chromatography (silica gel, with 1: 9 EtOAc/ hexane as eluent) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝1.19(t，J＝7.6Hz，3H)，1.47(d，J＝6.8Hz，3H)，2.54(q，J＝7.6Hz，2H)，3.74(s，3H)，4.04(bs，1H)，4.13(m，1H)，6.57(d，J＝8.5Hz，2H)，7.03(d，J＝8.4Hz，2H)。

¹³C-nmr(CDCl ₃)：δ＝15.8，18.0，27.9，52.17，52.19，113.5，128.6，134.1，144.4，175.3。

C ₁₂H ₁₇NO ₂(MW=207.27); Mass spectrum (MH ⁺) 208.

Embodiment A 28

Synthesizing of N-(4-(1-oxyethyl group) ethylphenyl) alanine methyl ester

According to the method for above embodiment A 27, separate title compound as another reaction product of column chromatography (silica gel, with 1: the 9EtOAc/ hexane is as eluent).

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝1.15(t，J＝7.0Hz，3H)，1.40(d，J＝6.5Hz，3H)，1.47(d，J＝6.1Hz，3H)，3.31(q，J＝5.1Hz，2H)，3.74(s，3H)，4.14(m，2H)，4.29(q，J＝6.4Hz，1H)，6.57(d，J＝8.5Hz，2H)，7.12(d，J＝8.4Hz，2H)。

¹³C-nmr(CDCl ₃)：δ＝15.4，19.0，23.9，51.9，52.2，63.4，77.3，113.1，127.3，133.6，145.8，175.1。

C ₁₄H ₂₁NO ₃(MW=251.33); Mass spectrum (MH ⁺) 251.

Embodiment A 29

N-(3, the 4-dichloro) L-Ala 2,2-dimethyl propyl ester (R, S isomer) synthetic

According to above transesterification universal method AQ, with N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from above embodiment A 9) and neopentyl alcohol (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction (Rf=0.72 launches in 25% EtOAc/ hexane).Carry out purifying through flash chromatography (silica gel, with the 25%EtOAc/ hexane as eluent).

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，1H，J＝8.7Hz)，6.68(d，1H)，J＝2.7Hz)，6.45(dd，1H，J＝8.7Hz，J＝2.7Hz)，4.29(m，1H)，4.11(m，1H)，3.85(m，2H)，1.49(d，3H，J＝6.9Hz)，0.93(s，9H).

¹³C-nmr(CDCl ₃)：δ＝174.6，146.7，133.5，131.3，121.3，114.9，113.7，75.2，52.4，32.0，26.9，19.4。

C ₁₄H ₁₉Cl ₂NO ₂(MW=304.22); Mass spectrum (MH ^-) 303.

Embodiment A 30

Synthesizing of N-(3, the 4-dichlorophenyl) glycine isobutyl ester

Adopt ordinary method to handle 3 with tert-Butyl dicarbonate (Aldrich), 4-dichlorphenamide bulk powder (Aldrich) produces N-BOC aniline.Handle described N-BOC aniline with the sodium hydride among the THF, use 2-bromide isobutyl acetate (deriving from above embodiment A D) to handle then, produce N-BOCN-(3, the 4-dichlorophenyl) glycine isobutyl ester.Adopt above universal method AN to remove the BOC group then, obtain title compound.By silica gel tlc monitoring reaction (Rf=0.78 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 50% EtOAc/ hexane as eluent) in the 50%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.19(d，J＝4.1，4.7，3.4，1H)，6.65(d，J＝2.7，1H)，6.44(dd，J＝2.75，4.5，4.2，1H)，4.4(m，1H)，3.97(dd，J＝3.6，3.0，2.3，2H)，3.87(s，2H)，1.9(m，1H)，0.93(d，J＝6.7，6H)。

¹³C-nmr(CDCl ₃)：δ＝171.2，147.0，133.5，131.3，121.2，114.5，113.3，72.2，46.0，28.2，19.6。

C ₁₂H ₁₅Cl ₂NO ₂(MW=276); Mass spectrum (MH ⁺) 277.

Embodiment A 31

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala 2-ethyl butyl ester

According to above universal method AA, with 3,4-dichlorphenamide bulk powder (Aldrich) and pyruvic acid 2-ethyl butyl ester (, replacing isopropylcarbinol to be prepared), preparation title compound oily matter with 2-ethyl butanol (Aldrich) according to universal method AO.By silica gel tlc monitoring reaction (Rf=0.6 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in the 25%EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2(d，1H)，6.6(d，1H)，6.4(dd，1H)，4.2(t，2H)，4.1(q，1H)，1.5(d，3H)，1.4(m，4H)，1.0(m，6H)。

¹³C-nmr(CDCl ₃)：δ＝178；144.7；130.2；120.62；115.11；70.7；51.90；26.3；19.53；18.5。

C ₁₅H ₂₁Cl ₂NO ₂(MW=318.25); Mass spectrum (MH ⁺) 319.

Embodiment A 32

Synthesizing of N-(3-chloro-4-iodophenyl) L-Ala isobutyl ester

According to above universal method AR, with 3-chloro-4-Iodoaniline (Aldrich) preparation N-BOC-3-chloro-4-Iodoaniline.Stir adding 1.0 equivalent N-BOC-3-chloro-4-Iodoanilines in the slurry to the DMF of 5.0 equivalent sodium hydrides, slowly add 1.1 equivalent 2 bromopropionic acid isobutyl esters (deriving from above embodiment A D) then.With reactant be heated to 100 ℃ 10 hours, cooling is with methylene dichloride dilution, with cold 1N HCl, water and salt water washing.Removal of solvent under reduced pressure, resistates obtain N-BOC-N-(3-chloro-4-iodophenyl) the transparent oily matter of L-Ala isobutyl ester through chromatographic separation.According to above universal method AN, remove the BOC group of N-BOC-N-(3-chloro-4-iodophenyl) L-Ala isobutyl ester, obtain title compound.Remove dereaction (Rf=0.58 launches) by silica gel tlc monitoring BOC-in 30% EtOAc/ hexane, carry out purifying through preparation property plate layer chromatography (silica gel, with the 30%EtOAc/ hexane as eluent).Described compound is further purified through HPLC chiral column chromatography (Chiralcel OD).

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.52(d，J＝8.7，1H)；6.72(d，J＝2.7，1H)；6.25(dd，J＝2.7，5.9，2.7，1H)；4.35(d，J＝6.6，1H)；4.08(quintex，J＝7.2，6.7，1H)；3.93(d，J＝6.7，2H)；1.94(m，1H)；1.47(d，J＝6.9，3H)；0.92(d，J＝6.9，6H)。

¹³C-nmr(CDCl ₃)：δ＝174.5，148.3，140.7，1?39.5，114.4，114.3，82.6，72.0，52.2，28.3，19.6，19.3。

C ₁₃H ₁₇ClINO ₂(MW=381.5); Mass spectrum (MH ⁺) 382.

Embodiment A 33

Synthesizing of N-(4-azido-phenyl) L-Ala isobutyl ester

According to above universal method AA, with 4-azido-aniline (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation) preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.3 (d, 2H), 6.8 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (septet, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

¹³C-nmr(CDCl ₃)：δ＝174.5，148.7，131.5，130.3，121.3，114.9，113.6，72.0，52.4，28.3，19.5，19.3。

C ₁₃H ₁₈N ₄O ₂(MW=262.31); Mass spectrum (MH ⁺) 263.

Embodiment A 34

The N-[(4-phenylcarbonyl group) phenyl] L-Ala isobutyl ester synthetic

According to above universal method AA, with 4 '-Uvinul A Plus (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 25% EtOAc/ hexane as eluent) in 25% EtOAc/ hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.7 (d, 2H), 7.1 (m, 5H), 6.9 (d, 2H), 4.30 (bs, 1H), 4.08 (q, 1H), 1.94 (septet, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

¹³C-nmr(CDCl ₃)：δ＝199，178.5，149.7，131.5，130.3，126，121.3，114.9，113.6，72.0，52.4，28.3，19.5，19.3。

C ₂₀H ₂₃NO ₃(MW=325.41); Mass spectrum (MH ⁺) 326.

Embodiment A 35

Synthesizing of N-(3, the 5-difluorophenyl) L-Ala isobutyl ester

According to above universal method AH, with N-(3, the 5-difluorophenyl) L-Ala (deriving from above embodiment A C) and isopropylcarbinol, preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.9 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 3% ethanol/methylene as eluent) in 3% ethanol/methylene.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.1(m，3H)，4.5(bs，1H)，4.1(d，1H)，3.95(m，2H)，2.0(m，1H)，1.5(d，J＝7Hz，3H)，0.95(d，J＝6Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝174.44，166.40，166.19，163.16，162.95，149.43，96.73，96.60，96.48，96.35，94.06，93.72，93.37，72.03，52.30，28.29，19.47，19.23。

C ₁₃H ₁₇F ₂NO ₂(MW=290.2); Mass spectrum (MH ⁺) 291.

Embodiment A 36

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala O-acyl group second amidoxim ester

According to above universal method AK, with N-(3, the 4-dichlorophenyl) L-Ala (deriving from above embodiment A B) and second amidoxim (according to J.Org.Cehm., the preparation of method described in 46,3953 (1981)), preparation title compound semisolid.By silica gel tlc monitoring reaction (Rf=0.4 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with ethyl acetate as eluent) in ethyl acetate.

The NMR data are as follows:

¹H-nmr (DMSO-d ₆): δ=7.27 (d, 1H), 6.81 (s, 1H), 6.4 (wide s, 2H), 6.62 (d, 1H), 6.45 (d, 1H), 4.22 (m, 1H), 1.74 (s, 3H), 1.40 (d, 3H).

C ₁₁H ₁₃Cl ₂N ₃O ₂(MW=290.15); Mass spectrum (MH ^-) 291.

Embodiment A 37

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala pyrrole amides

According to above universal method AL, with N-(3, the 4-dichlorophenyl) L-Ala (deriving from above embodiment A B) and pyrroles (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.28 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 10% ethyl acetate/hexane as eluent) in 10% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.36(d，J＝2.2，2H)，7.20(d，J＝8.7，1H)，6.71(d，J＝2.7，1H)，6.5(m，1H)，6.38(t，J＝2.4，2H)，4.8(m，1H)，4.57(d，J＝8.7，1H)，1.59(d，J＝6.8，3H)。

¹³C-nmr(CDCl ₃)：δ＝171.9，146.1，133.6，131.5，121.9，119.6，115.4，114.7，113.8，51.8，20.2。

C ₁₃H ₁₂Cl ₂N ₂O (MW=283); Mass spectrum (MH ⁺) 284.

Embodiment A 38

Synthesizing of N-(3, the 4-dichlorophenyl) L-Ala O-acyl group fourth amidoxim ester

According to above universal method AI, with N-(3, the 4-dichlorophenyl) L-Ala 2,4,6-trichlorophenyl ester (adopts and the described basic identical method of above embodiment A E, by N-(3, the 4-dichlorophenyl) alanine methyl ester (deriving from embodiment A 9) preparation) and the fourth amidoxim (according to J.Org.Chem., the preparation of method described in 46,3953 (1981)), preparation title compound semisolid.By silica gel tlc monitoring reaction (Rf=0.25 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with 50% ethyl acetate/hexane as eluent) in 50% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (d ₆-DMSO): δ=7.27 (d, 1H), 6.83 (s, 1H), 6.38 (wide s, 2H), 6.61 (d, 1H), 6.46 (d, 1H), 4.25 (m, 1H), 2.02 (t, 2H), 1.55 (m, 2H), 1.40 (d, 3H), 0.88 (t, 3H).

C ₁₃H ₁₇Cl ₂N ₃O ₂(MW=318.20); Mass spectrum (MH ⁺) 319.

Embodiment A 39

2-[N-(naphthalene-2-yl) amino] ethyl butyrate synthetic

According to above universal method AJ, with 2-amino naphthalenes (Aldrich) and 2-bromo-butyric acid ethyl ester (Aldrich), preparation title compound solid, its fusing point is 81-83 ℃.By silica gel tlc monitoring reaction (Rf=0.5 launches), carry out purifying through preparation property plate layer chromatography (silica gel, with chloroform as eluent) in chloroform.

The NMR data are as follows: ¹H-nmr (d ₆-DMSO): δ=7.63 (m, 2H), 7.54 (d, 1 H), 7.31 (t, 1H), 7.12 (t, 1H), 7.03 (d, 1H), 6.62 (s, 1H), 6.32 (d, 1H), 4.15 (m, 3H), 1.42 (d, 3H), 1.19 (t, 3H).

C ₁₆H ₁₉NO ₂(MW=257.34); Mass spectrum (MH ⁺) 258.

Embodiment A 40

(the 2-naphthalene-yl) the L-Ala isobutyl ester is synthetic for N-

According to above universal method AA, with 2-amino naphthalenes (Aldrich) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound oily matter.Carry out purifying through preparation property plate layer chromatography (silica gel, with 25% ethyl acetate/hexane as eluent).

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.65 (m, 3H), 7.38 (t, 1H, J=6.9Hz), 7.23 (t, 1H, J=6.9Hz), 6.93 (m, 1H), 6.81 (d, 1H, J=2.3Hz), 4.31 (q, 1H, J=6.9Hz), 3.95 (J=6.7Hz, J=1.6Hz), 1.96 (septet, 1H, J=6.7Hz), 1.57 (d, 3H, J=6.9Hz), 0.93 (dd, 6H, J=6.7Hz, J=1.6Hz).

¹³C-nmr(CDCl ₃)：δ＝174.6，144.2，134.9，129.1，127.8，127.6，126.3，126.0，122.3，118.1，105.3，71.2，52.0，27.7，18.9，18.8。

Embodiment A 41

Synthesizing of N-(2-toluquinoline-6-yl) L-Ala isobutyl ester

According to above universal method AA, with 6-amino-2-methyl quinoline (Lancaster) and pyruvic acid isobutyl ester (according to above universal method AO preparation), preparation title compound.By silica gel tlc monitoring reaction (Rf=0.44 launches with 50% EtOAc/ hexane).Carry out purifying through flash chromatography (silica gel, with 50% ethyl acetate/hexane as eluent).

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.90 (m, 2H), 7.10 (m, 2H), 6.66 (d, 1H, J=2.6), 4.50 (bd, 1H), 4.24 (m, 1H), 3.91 (d, 2H, J=6.6Hz), 2.64 (s, 3H), 1.91 (septets, 1H, J=6.7Hz), 1.52 (d, 3H, J=6.9Hz), 0.87 (d, 6H, J=6.7Hz).

¹³C-nmr(CDCl ₃)：δ＝175.0，155.4，144.6，143.4，134.9，130.2，128.4，122.8，121.8，104.9，71.8，52.7，28.3，25.4，19.5，19.4。

C ₁₇H ₂₂Cl ₂N ₂O ₂(MW=286.38); Mass spectrum (MH ⁺) 287.

Embodiment A 42

Synthesizing of N-(3,4-methylenedioxyphenyl base) L-Ala isobutyl ester

According to above reduction amination universal method AA, with 3,4-methylenedioxyphenyl amine (Aldrich) and Pyruvic Acid Methyl ester (Aldrich), preparation N-(3,4-methylenedioxyphenyl base) alanine methyl ester.According to above universal method AQ, adopt isopropylcarbinol to carry out the transesterification of methyl esters then, obtain title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.61 launches),, carry out purifying as eluent with 25% ethyl acetate/hexane through preparation property plate silica gel column chromatography purifying in 25% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=6.63 (d, 1H, 8.3Hz), 6.25 (d, 1H, J=2.3Hz), 6.04 (dd, 1H, J=8.3Hz, J=2.3Hz), 5.83 (s, 2H), 3.96 (m, 4H), 1.92 (septet, 1H, J=6.7Hz), 1.44 (d, 3H, J=6.9Hz), 0.90 (d, 6H, J=6.6Hz).

¹³C-nmr(CDCl ₃)：δ＝175.4，148.9，142.9，140.8，109.2，105.8，101.2，97.4，71.6，53.6，28.3，19.6，19.5。

C ₁₄H ₁₉NO ₄(MW=265.31); Mass spectrum (MH ⁺) 265.

Embodiment A 43

Synthesizing of N-(3,4-ethylenedioxy phenyl) L-Ala isobutyl ester

According to above reduction amination universal method AA, with 1,4-benzo two oxa-s-6-amine (Aldrich) and Pyruvic Acid Methyl ester (Aldrich), preparation N-(3,4-ethylenedioxy phenyl) alanine methyl ester.According to above universal method AQ, adopt isopropylcarbinol to carry out the transesterification of methyl esters then, obtain title compound.Through preparation property plate silica gel column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.91(d，J＝7Hz，6H)，1.42(d，J＝7Hz，3H)，1.8-2.0(m，1H)，3.8-3.95(m，3H)，4.0-4.1(m，1H)，4.15-4.25(m，4H)，6.12-6.2(m，2H)，6.65-6.75(m，1H)。

¹³C-nmr(CDCl ₃)：δ＝19.55，19.56，19.67，28.3，53.4，64.7，65.3，71.7，103.1，108.0，118.3，142.1，144.6，175.4。

C ₁₅H ₂₁NO ₄(MW=279.34); Mass spectrum (MH ⁺) 280.

Embodiment A 44

Synthesizing of N-(2-naphthyl) alanine methyl ester

According to above reduction amination universal method AA, with 2-amino naphthalenes (Aldrich) and Pyruvic Acid Methyl ester (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction (Rf=0.50 launches in 25% ethyl acetate/hexane).Through flash chromatography on silica gel, carry out purifying as eluent with 25% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.65(m，3H)，7.48(m，1H)，7.25(m，1H)，6.91(m，1H)，6.79(m，1H)，4.31(m，2H)，3.76(s，3H)，1.55(d，3H)。

¹³C-nmr(CDCl ₃)：δ＝175.66，144.78，135.55，129.78，128.47，128.22，126.96，126.67，123.01，118.66，105.88，52.95，52.51，19.45。

C ₁₄H ₁₅NO ₂(MW=229.28); Mass spectrum (MH ⁺) 229.

Embodiment A 45

Synthesizing of N-(benzothiazole-6-yl) alanine ethyl ester

In the dichloromethane solution of 6-aminobenzothiazole (Lancaster), add 1.2 equivalent pyridines, add 1.5 equivalent trifluoroacetic anhydrides then.Reactant was stirred under room temperature 3 hours,,, on rotatory evaporator, remove and desolvate, produce 6-trifluoroacetamido thiazole through dried over mgso then with the washing of 5% citric acid.This material is dissolved among the THF, then in the THF suspension of 0 ℃ of adding KH.Add the hexaoxacyclooctadecane-6-6 of catalytic amount, add 2 bromopropionic acid ethyl ester (Aldrich) then.Reactant was kept under room temperature 1 hour, and reflux is 24 hours then, is cooled to room temperature then.On rotatory evaporator, remove the solvent in the reaction mixture, the resistates that produces is dissolved in ether.This solution with water, saturated sodium-chloride water solution washing, and through dried over mgso.Remove the solvent in this solution on rotatory evaporator, resistates as eluent, obtains title compound with 5% ethanol/methylene (Rf=0.59) through chromatographic separation.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.69(s.1H)，7.90(d，1H，J＝8.8Hz)，7.04(d，1H，J＝2.3Hz)，6.84(dd，1H，J＝8.8Hz，J＝2.4Hz)，4.41(bd，1H，J＝7.5Hz)，4.20(m，3H)，1.53(d，3H，J＝6.9Hz)，1.27(t，3H，J＝7.1Hz)。

¹³C-nmr(CDCl ₃)：δ＝174.9，150.2，147.1，145.6，136.3，124.6，115.7，103.5，61.9，52.9，19.4，14.8。

C ₁₂H ₁₄N ₂O ₂S (MW=250.32); Mass spectrum (MH ⁺) 251.

Embodiment A 46

Synthesizing of N-(indoles-5-yl) L-Ala isobutyl ester (S isomer)

According to above universal method AM, with 5-amino indole (Aldrich) and R-(+)-isobutyl lactate (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.46 launches in 33% ethyl acetate/hexane).Through the preparation of silica gel plate layer chromatography, carry out purifying as eluent with 33% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=8.11 (bs, 1H), 7.07 (d, J=8.8Hz, 1H), 6.98 (d, J=2.8Hz, 1H), 6.83 (d, J=2.2Hz, 1H), 6.61 (m, 1H), 6.32 (m, 1H), 4.18 (q, J=6.9Hz, 1H), 3.95 (bs, 1H), 3.87 (d, J=6.7Hz, 2H), 1.89 (septet, J=6.7Hz, 1H), 1.48 (d, J=6.96Hz, 3H), 0.86 (dd, J=6.7Hz, J=1.6Hz, 6H).

¹³C-nmr(CDCl ₃)：δ＝176.15，141.06，131.28，129.24，125.34，113.34，112.53，104.21，102.17，71.65，54.28，28.36，19.87，19.62。

C ₁₅H ₂₀N ₂O ₂(MW=260.34); Mass spectrum (MH ⁺) 261.

Embodiment A 47

Synthesizing of N-(naphthyl-2-yl) L-Ala O-acyl group second amidoxim ester

According to above universal method AI, with N-(naphthalene-2-yl) L-Ala 2,4,6-trichlorophenyl ester (deriving from above embodiment A E) and second amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound semisolid.By silica gel tlc monitoring reaction (Rf=0.4 launches in ethyl acetate).Carry out purifying through preparation property silica-gel plate chromatography (with ethyl acetate as eluent).

The NMR data are as follows:

¹H-nmr (d ₆-DMSO): δ=7.64 (t, 2H), 7.54 (d, 1H), 7.32 (t, 1H), 7.13 (t, 1H), 7.04 (d, 1H), 6.78 (s, 1H), 6.42 (wide s, 2H), 6.32 (d, 1H), 4.33 (m, 1H), 1.72 (s, 3H), 1.46 (d, 3H).

C ₁₅H ₁₇N ₃O ₂(MW=271.32); Mass spectrum 271.

Embodiment A 48

Synthesizing of N-(2-naphthyl) alanine ethyl ester

According to above reduction amination universal method AA, with 2-amino naphthalenes (Aldrich) and Pyruvic Acid Ethyl ester (Aldrich), preparation title compound solid, its fusing point is 52-56 ℃.By silica gel tlc monitoring reaction (Rf=0.50 launches in 25% ethyl acetate/hexane).Through flash chromatography on silica gel, carry out purifying as eluent with 25% ethyl acetate/hexane.

The NMR data are as follows:

C ₁₄H ₁₅NO ₂(MW=229.28); Mass spectrum (MH ⁺) 229.

Embodiment A 49

Synthesizing of N-(3, the 4-dichlorophenyl) the L-Ala O-acyl group third amidoxim ester

According to above universal method AI, with N-(3, the 4-dichlorophenyl) L-Ala 2,4, and 6-trichlorophenyl ester (adopts and essentially identical method described in the above embodiment A E, by N-(3, the 4-dichlorophenyl) alanine methyl ester prepares) and third amidoxim (according to J.Org, Chem., 46, the preparation of method described in 3953 (1981)), preparation title compound semisolid.By silica gel tlc monitoring reaction (Rf=0.2 launches in 50% ethyl acetate/hexane).Through the preparation of silica gel plate layer chromatography, carry out purifying as eluent with 50% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (d ₆-DMSO): δ=7.27 (d, 1H), 6.83 (s, 1H), 6.64 (d, 1H), 6.47 (d, 1H), 6.28 (wide s, 2H), 4.24 (m, 1H), 2.07 (q, 2H), 1.41 (d, 3H).

C ₁₂H ₁₅Cl ₂N ₃O ₂(MW=304.17); Mass spectrum (MH ⁺) 305.

Embodiment A 50

Synthesizing of N-(4-ethoxycarbonyl phenyl) L-Ala isobutyl ester (S isomer)

According to above universal method AM, with 4-subcutin (Aldrich) and R-(+)-isobutyl lactate (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.21 launches in 10% ethyl acetate/hexane).Through the preparation thin-layer chromatography, carry out purifying as eluent with 25% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.82 (d, J=8.73Hz, 2H), 6.51 (d, J=8.79Hz, 2H), 4.81 (d, J=7.82Hz, 1H), 4.25 (q, J=7.14Hz, 2H), 4.15 (quint, J=7.40Hz, 1H), 3.87 (m, 2H), 1.87 (septet, J=6.70Hz, 1H), 1.43 (d, J=6.95Hz, 3H), 1.30 (t, J=7.14Hz, 3H), 0.84 (d, J=6.71Hz, 6H).

¹³C-nmr(CDCl ₃)：δ＝174.5，167.3，151.0，132.0，119.9，112.5，71.9，60.8，51.9，28.2，19.5，19.2，15.0。

C ₁₆H ₂₃NO ₄(MW=293.37); Mass spectrum (MH ⁺) 294.

Embodiment A 51

Synthesizing of N-(3,5-two (trifluoromethyl) phenyl) L-Ala isobutyl ester (S isomer)

According to above universal method AM, with 3,5-two (trifluoromethyl) aniline (Aldrich) and R-(+)-isobutyl lactate (Aldrich), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.38 launches in 10% ethyl acetate/hexane).Carry out purifying through preparation property plate layer chromatography (silica gel, with 10% ethyl acetate/hexane as eluent).

The NMR data are as follows:

¹H-nmr (CDCl ₃): δ=7.13 (s, 1H), 6.91 (s, 2H), 4.97 (d, J=8.24Hz, 1H), 4.18 (m, 1H), 3.93 (d, J=6.59Hz, 2H), 1.93 (septet, J=6.71Hz, 1H), 1.49 (d, J=7.02Hz, 3H), 0.89 (d, J=6.59Hz, 6H).

¹³C-nmr(CDCl ₃)：δ＝174.4，147.9，133.6，133.2，132.7，132.3，129.4，125.8，122.2，118.6，112.81，112.76，111.42，11137，111.32，111.27，111.22，72.2，52.0，32.1，28.24，28.17，23.2，19.5，19.3，19.2，18.9，14.6。

C ₁₅H ₁₇F ₆NO ₂(MW=357.30); Mass spectrum (MH ⁺) 358.

Embodiment A 52

Synthesizing of N-(3, the 5-Dimethoxyphenyl) L-Ala isobutyl ester

In dry isobutanol (10ml), handle N-(3 with 0.1ml chloro trimethyl silane, the 5-Dimethoxyphenyl) L-Ala (crude product, 454mg) (according to United States Patent (USP) the 3rd, 598, method described in No. 859, with 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich) preparation), reaction mixture refluxed is spent the night.Excessive alcohol is removed in decompression, and resistates is dissolved in the ethyl acetate.Wash ethyl acetate solution with saturated sodium bicarbonate aqueous solution, use dried over sodium sulfate, remove and desolvate, title compound is provided.By silica gel tlc monitoring reaction (Rf=0.3 launches in 20% ethyl acetate/hexane).Through the preparation of lamina chromatography, carry out purifying as eluent with 20% ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.9(d，J＝7，6H)，1.47(d，J＝7，3H)，1.9-2.0(m，1H)，3.7(s，6H)，3.85-4.0(m，2H)，4.1-4.2(m，1H)，4.3(brs，1H)，5.8(s，2H)，5.9(s，1H)。

¹³C-nmr(CDCl ₃)：δ＝19.49，19.52，19.54，28.3，52.5，55.6，71.7，91.1，92.7，149.2，162.3，175.2。

C ₁₅H ₂₃NO ₄(MW＝281.35)。

Embodiment A 53

Synthesizing of N-(2-naphthyl) the L-Ala O-acyl group third amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4, the 5-trichlorophenyl ester (deriving from above embodiment A E) and third amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound.By silica gel tlc monitoring reaction (Rf=0.5 launches in ethyl acetate).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(d ₆-DMSO)：δ＝1.03(t，3H)，1.45(d，3H)。

C ₁₆H ₁₉N ₃O ₂(MW=285.35); Mass spectrum (MH ⁺) 285.

Embodiment A 54

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group fourth amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and fourth amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.6 launches in ethyl acetate).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝0.86(t，3H)，1.46(d，3H)。

C ₁₇H ₂₁N ₃O ₂(MW=299.37); Mass spectrum (MH ⁺) 299.

Embodiment A 55

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group isoamyl amidoxim ester

According to universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and isoamyl amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launched in the ethyl acetate/hexane at 1: 1).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(d ₆-DMSO)：δ＝0.86(t，3H)，1.45(d，3H)。

C ₁₈H ₂₃N ₃O ₂(MW=313.40); Mass spectrum (MH ⁺) 313.

Embodiment A 56

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group benzene first amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and benzene first amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launched in the ethyl acetate/hexane at 1: 1).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(d ₆-DMSO)：δ＝4.42(m，1H)，1.53(d，3H)。

C ₂₀H ₁₉N ₃O ₂(MW=333.39); Mass spectrum (MH ⁺) 333.

Embodiment A 57

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group cyclopropane first amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and cyclopropane first amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launched in the ethyl acetate/hexane at 1: 1).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(d ₆-DMSO)：δ＝0.85(m，4H)，1.43(d，3H)。

C ₁₇H ₁₉N ₃O ₂(MW=297.36); Mass spectrum (MH ⁺) 297.

Embodiment A 58

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group cyclopropyl second amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and cyclopropyl second amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launched in the ethyl acetate/hexane at 1: 1).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(d ₆-DMSO)：δ＝1.43(d，3H)，1.91(d，2H)。

C ₁₈H ₂₁N ₃O ₂(MW=311.39); Mass spectrum (MH ⁺) 311.

Embodiment A 59

Synthesizing of N-(2-naphthyl) L-Ala O-acyl group pentamethylene first amidoxim ester

According to above universal method AS, with N-(2-naphthyl) L-Ala 2,4,5-trichlorophenyl ester (deriving from above embodiment A E) and pentamethylene first amidoxim (according to J.Org, Chem., the preparation of method described in 46,3953 (1981)), preparation title compound oily matter.By silica gel tlc monitoring reaction (Rf=0.3 launched in the ethyl acetate/hexane at 1: 1).Through silica gel column chromatography, carry out purifying as eluent with 1: 1 ethyl acetate/hexane.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.43(d，3H)，2.43(m，1H)。

C ₁₇H ₁₉N ₃O ₂(MW＝297.36)。

Universal method BA

R ¹C (X ') (and X ") C (O) Cl and H ₂NCH (R ²) C (O) XR ³Coupling

To (D, L)-add the acyl chlorides of 4.6mmol in L-Ala isobutyl ester hydrochloride (deriving from following examples BB) the 5ml pyridine stirred solution (4.6mmol).Produce precipitation immediately.Mixture was stirred 3.5 hours,,,, wash 1 time with 20% salt of wormwood with salt water washing 1 time with 10%HCl washing 3 times with the dilution of 100ml ether, and with salt water washing 1 time.This solution through dried over mgso, is filtered and reduction vaporization, produce this product.Other amino acid ester also can be used for this method.

Universal method BB

R ¹C (X ') (and X ") C (O) OH and H ₂NCH (R ²) C (O) XR ³Coupling

With the 20ml THF solution stirring of described acid (3.3mmol) and CDI 2 hours.Add L-L-Ala isobutyl ester hydrochloride (deriving from following examples BB) (3.6mmol), add 1.5ml (10.8mmol) triethylamine then.The reaction mixture stirring is spent the night.Reaction mixture is with the dilution of 100ml ether, with 10%HCl washing 3 times, with salt water washing 1 time, with 20% salt of wormwood washing 1 time, with salt water washing 1 time.This solution through dried over mgso, is filtered and reduction vaporization, produce this product.Other amino acid ester also can be used for this method.

Universal method BC

Use HOR ³Carry out R ¹C (X ') (and X ") C (O) NHCH (R ²) esterification of C (O) OH

(1.6470g, (1.05g 6.5mmol), stirs mixture 1.5 hours to add CDI in 20ml THF stirred solution 7.0mmol) to the phenylacetyl Xie Ansuan.With the 2-methyl butanol (0.53g 6mmol) adds in the mixture, add then sodium hydride (0.16g, 6.5mmol).Produce bubble immediately.The reaction mixture stirring is spent the night.Reaction mixture is with the dilution of 100ml ether, with 10%HCl washing 3 times, with salt water washing 1 time, with 20% salt of wormwood washing 1 time, with salt water washing 1 time.This solution through dried over mgso, is filtered and reduction vaporization, produce this product.Other N-acylamino acid and alcohol also can be used for this method.

Universal method BD

Ester is hydrolyzed to free acid

By ordinary method ester is hydrolyzed to free acid.Below be 2 embodiment that this class routine is taken off the ester method.

Methanol to described ester in mixture adds 2-5 equivalent salt of wormwood at 1: 1.Mixture heating up to about 50 ℃ of about 0.5-1.5 hours, is finished until tlc demonstration reaction.Reactant is cooled to room temperature, and methyl alcohol is removed in decompression.The pH of remainder water solution is transferred to about 2, add this product of ethyl acetate extraction.Organic phase is with the saturated sodium-chloride water solution washing and through dried over mgso then.The solvent in the solution is removed in decompression, produces this product.

Described amino acid ester is dissolved in diox/water (4: 1), add LiOH soluble in water (～2eq.), make adding the back total solvent is about 2: 1 dioxs: water.Stirred reaction mixture is finished until reaction, and diox is removed in decompression.Resistates dilutes with ethyl acetate, separates each layer, and water layer is acidified to pH 2.Water layer is stripped with ethyl acetate, and the organism of merging filters the back removal of solvent under reduced pressure through dried over sodium sulfate.Resistates ordinary method purifying (for example recrystallization).

Below exemplify this back one embodiment.With 3-NO ₂The methyl esters 9.27g (0.0348mol) of phenylacetyl L-Ala is dissolved in 60ml diox and the 15ml water, add the LiOH be dissolved in the 15ml water (3.06g, 0.0731mol).Stir after 4 hours, diox is removed in decompression, and resistates dilutes with ethyl acetate, separates each layer, and water layer is acidified to pH 2.Water layer is stripped with ethyl acetate, and (4 * 100ml), the organism of merging filters the back removal of solvent under reduced pressure through dried over sodium sulfate.Resistates is recrystallization from ethyl acetate/octane-iso, produces 7.5g (85%) 3-oil of mirbane ethanoyl L-Ala.C ₁₁H ₁₂N ₂O ₅Calculated value: C=52.38, H=4.80, and N=11.11.Analyze measured value: C=52.54, H=4.85, and N=11.08.[α] ₂₃=-29.9 in 589nm.

Universal method BE

The low temperature BOP coupling of acid and alcohol

Under nitrogen, the dichloromethane solution that will contain described carboxylic acid (100M%) and N-methylmorpholine (150M%) is cooled to-20 ℃.Once add BOP (105M%), reaction mixture was kept 15 minutes in-20 ℃.Add corresponding alcohol (120M%), allow the reaction mixture temperature to room temperature, and stirred 12 hours.Reaction mixture is injected water, with ethyl acetate extraction (3 *).The ethyl acetate that merges partly uses saturated aqueous citric acid solution (2 *), saturated sodium bicarbonate aqueous solution (2 *), salt solution (1 *) to strip, and through anhydrous magnesium sulfate or dried over sodium sulfate, removal of solvent under reduced pressure produces described crude product.

Universal method BF

The EDC coupling of acid and amine

Described acid derivative is dissolved in the methylene dichloride.Order adds described amine (1eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2eq.).Reactant is cooled to about 0 ℃, adds 1.2eq.1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride then.This solution stirring is spent the night, and be issued to room temperature at nitrogen pressure.By with saturated aqueous sodium carbonate, 0.1M citric acid and this solution of salt water washing, with dried over sodium sulfate and except that desolvating reaction mixture, produce crude product then.Obtain pure products through flash chromatography in suitable solvent.

Universal method BG

The EDC coupling of acid and amine

Under nitrogen atmosphere, in round-bottomed flask, add the THF solution of carboxylic acid (1.0eq.), hydroxy benzotriazole hydrate (1.1eq.) and amine (1.0eq.).Will be an amount of the alkali (as HunigShi alkali) of (is 1.1eq. for unhindered amina, and be 2.2eq. for amine hydrochlorate) add in the well-beaten mixture, add EDC (1.1eq.) then.After stirring 4-17 hour under the room temperature, removal of solvent under reduced pressure is absorbed into resistates in ethyl acetate (or similar solvent)/water.Organic layer adopts saturated sodium bicarbonate aqueous solution, 1N HCl, salt water washing, and through anhydrous sodium sulfate drying.In some cases, isolating product is an analytical pure in this stage, and in other cases, before biological assessment, needs by chromatography and/or recrystallization purifying.

Universal method BH

R ¹C (X ') (and X ") C (O) Cl and H ₂NCH (R ²) C (O) XR ³Coupling

The dichloromethane solution of excessive oxalyl chloride is added in the derivative of described acid with a DMF.With the mixture stir about that produces 2 hours, or until stopping to produce bubble.Removal of solvent under reduced pressure is heavily diluted with anhydrous methylene chloride then.In the solution that produces, add suitable amino acid ester and the triethylamine (dichloromethane solution of 1.1eq.) of about 1.1eq..This system was stirred under room temperature 2 hours, then removal of solvent under reduced pressure.Resistates is dissolved in the ethyl acetate, with 1N HCl washing, then with 1N NaOH washing.Organic layer filters and removal of solvent under reduced pressure through anhydrous sodium sulfate drying, obtains required product.

Universal method BI

The P-EPC coupling

The acetic acid compound of amino acid ester and replacement is used in the P-EPC coupling.Described acetogenin is well known in the art, and is normally commercially available.Use ordinary method, prepare described amino acid ester by known and common commercially available N-BOC amino acid, described in described N-BOC amino acid such as the following universal method BJ.

Specifically, suitable amino ester free alkali (0.0346mmol) and substituted phenylacetic acid (0.069mmol) are dissolved in the 2.0ml chloroform (no ethanol), handle, reactant was mixed 4 days in 23 ℃ with 150mg P-EPC (0.87meq./g).Reactant is filtered, with the flushing of 2.0ml chloroform, evaporated filtrate under nitrogen gas stream by tampon.The purity of every kind of sample is passed through ¹H NMR measures, and scope is 50% to＞95%.Obtain the 8.0-15.0mg end product by each reaction, test without other purifying.

Universal method BJ

Esterification by corresponding N-described acid of BOC amino acid synthesizing amino acid esters A.

N-BOC amino acid is dissolved in the diox, in 0 ℃ with excessive alcohol (～1.5eq.) and catalysis DMAP (100mg) handle.Continue to stir, finish until reaction, reclaim described product with ordinary method this moment.B. remove the N-BOC group

The amino acid of N-BOC protection is dissolved in the methylene dichloride (0.05M), under nitrogen atmosphere, room temperature, handles with 10eq.TFA.By the tlc monitoring reaction, intact until raw material consumption, usually in 1-5 hour.If still have raw material after 5 hours, again 10eq.TFA added in the reactant.With yellow soda ash neutralization reactant carefully, separate, organic layer salt water washing, and through anhydrous sodium sulfate drying.Described then crude product amine is purified and use.

The concrete example of these methods is as follows:

With racemize (+/-)-N-BOC-butyrine (Aldrich) (9.29g 0.0457mol) is dissolved in the 100ml diox, in 0 ℃ with isopropylcarbinol (6.26ml, 0.0686mol), EDC (8.27g, 0.0457) and catalysis DMAP (100mg) handle.Stir after 17 hours, the reduction vaporization organism, resistates dilutes with ethyl acetate, with sodium bicarbonate, salt water washing, and through dried over sodium sulfate.Evaporation produces 8.42g (71%) oily matter.C ₁₃H ₂₅NO ₄Calculated value: C=60.21, H=9.72, and N=5.40.Analyze measured value: C=59.91, H=9.89, and N=5.67.

(8.00g 0.032mol) goes protection, obtains the described free alkali of 3.12g (61%), and this free alkali is a colorless oil, solidifies when leaving standstill with above N-BOC amino acid ester as mentioned above.

With L-N-BOC L-Ala (Aldrich) (8.97g, 0.047mol) be dissolved in 100ml methylene dichloride, isopropylcarbinol (21.9ml, 0.238mol) in, (10.0g is 0.52mol) in 0 ℃ of processing with DMAP (100mg) and EDC.Mixture was stirred 17 hours, and dilute with water washs successively with 1.0NHCl, sodium bicarbonate and salt solution, and organism is through dried over sodium sulfate.Filter and evaporation generation 11.8g (quantitatively) L-N-BOC L-Ala isobutyl ester, the latter is mixed with a small amount of solvent.The vacuum-drying sample is used for analytical analysis.C ₁₂H ₂₃NO ₄Calculated value: C=58.79, H=9.38, and N=5.71.Analyze measured value: C=58.73, H=9.55, and N=5.96.

(11.8g 0.0481mol) goes protection with above N-BOC amino acid ester as mentioned above.With saturated HCl (g)/EtOAc described free alkali is converted into corresponding hydrochloride, obtains L-N-L-Ala isobutyl ester hydrochloride.Obtain 4.2g (48%) colorless solid.C ₇H ₁₅NO ₂HCl calculated value: C=46.28, H=8.88, and N=7.71.Analyze measured value: C=46.01, H=8.85, and N=7.68.

Universal method BK

Form methyl esters by amino acid

Described amino acid (amino acid or amino acid salts hydrochlorate) is suspended in the methyl alcohol, is cooled to 0 ℃.HCl gas was fed in this solution 5 minutes.Allow the reactant temperature to room temperature, stirred then 4 hours.Removal of solvent under reduced pressure obtains amino acid needed methyl ester hydrochloride then.This product uses without being further purified usually.

Embodiment B A

Free PEPC and polymkeric substance are in conjunction with synthetic N-ethyl-N '-3-(1-pyrrolidyl) third urea of PEPC

Under cooling, Dropwise 5 0g (0.39mol) 3-(1-pyrrolidyl) propylamine in the 250ml chloroformic solution of 27.7g (0.39mol) ethyl isocyanate.Finish in case add, then remove cooling bath, reaction mixture was stirred under room temperature 4 hours.Concentrating under reduced pressure reaction mixture then obtains the transparent oily matter of required urea of 74.5g (96.4%).1-(3-(1-pyrrolidyl) propyl group)-3-ethyl carbodiimide (P-EPC)

In the 500ml dichloromethane solution of 31.0g (0.156mol) N-ethyl-N '-3-(1-pyrrolidyl) third urea, add 62.6g (0.62mol) triethylamine, and this solution is cooled to 0 ℃.The 400ml dichloromethane solution of Dropwise 5 9.17g (0.31mol) 4-toluene sulfonyl chloride in this solution then adds speed and makes reactant is maintained at 0-5 ℃.After adding is finished, the reaction mixture temperature to room temperature, is heated to then and refluxed 4 hours.After being cooled to room temperature, (3 * 150ml) wash reaction mixture with the unsaturated carbonate aqueous solutions of potassium.Merge water, use dichloromethane extraction.Merge all organic phases, and concentrating under reduced pressure.The orange slurry that produces is suspended in the 250ml ether, and the solution that inclines stays solid.Slurry/decant process is repeated 3 times again.Merge diethyl ether solution, and concentrating under reduced pressure, the required product crude product of 18.9g (67%) orange obtained.With the distillation of oily matter partial vacuum, obtain colorless oil in 78-82 ℃ (0.4mm Hg).The preparation of the 1-of polymkeric substance its load form (3-(1-pyrrolidyl) propyl group)-3-ethyl carbodiimide (P-EPC)

(2% is crosslinked with 8.75g (48.3mmol) 1-(3-(1-pyrrolidyl) propyl group)-3-ethyl carbodiimide and 24.17g (24.17mmol) MerrifieldShi resin, the 200-400 order, chloromethylation vinylbenzene/divinylbenzene copolymer, dimethyl formamide suspension 1meq.Cl/g) was in 100 ℃ of heating 2 days.With the reactant cooling, filter, the resin of generation is in proper order with 1L DMF, 1L THF and the washing of 1L ether.Remaining then resin vacuum-drying 18 hours.

Embodiment B B

The preparation of L-Ala isobutyl ester hydrochloride

With 35.64g (0.4mol) (D, L)-mixture of L-Ala (Aldrich) (or L-L-Ala (Aldrich)), 44ml (0.6mol) thionyl chloride (Aldrich) and 200ml isopropylcarbinol refluxed 1.5 hours, volatile matter is removed in decompression fully on 90 ℃ of rotatory evaporators, obtain (D, L)-and L-Ala isobutyl ester hydrochloride (or L-L-Ala isobutyl ester hydrochloride), the latter's purity is enough to be used in further conversion.

Embodiment B C

3, the preparation of 5-fenac

To 0 ℃ 3.5g 3, add the 1.8ml methylsulfonyl chloride in the 75ml dichloromethane solution of 5-Dybenal (Aldrich), then, drip the 3.5ml triethylamine.After 2 hours, with methylene dichloride with this solution dilution to 150ml, with 3N HCl, saturated sodium bicarbonate aqueous solution washing, use dried over sodium sulfate, and remove and desolvate, obtain required methylsulfonic acid 3,5-benzyl dichloride ester yellow oil, described oily matter is purified and use.

The crude product sulphonate is dissolved among the 50ml DMF in 0 ℃, adds 3g KCN then.After 2 hours, add other 50ml DMF, with this solution stirring 16 hours.This red solution dilutes with 1 premium on currency, is acidified to pH 3 with 3N HCl.With this aqueous solution of dichloromethane extraction.The organism that merges with dried over sodium sulfate and removal of solvent under reduced pressure, obtains crude product 3 with 3N HCl washing, 5-dichlorophenyl acetonitrile, and the latter uses without purifying.

Described nitrile is added in the mixture of the 40ml vitriol oil and 50ml water, and be heated to and refluxed 48 hours, it is cooled to room temperature and stirred 48 hours.Reactant is diluted in 1 liter of trash ice, and temperature is to room temperature, and with 2 * 200ml methylene dichloride and 2 * 200ml ethyl acetate extraction.2 groups of organism are merged, wash with saturated sodium bicarbonate aqueous solution.Merge the sodium bicarbonate part, and be acidified to pH 1 with 3N HCl.White solid is too thin, can not filter, and goes out with 2 * 200ml dichloromethane extraction.The organism dried over sodium sulfate that merges, removal of solvent under reduced pressure obtains crude product 3,5-fenac white solid.Described solid is made slurry with hexane, filters to obtain the 1.75g white solid.

NMR (CDCl ₃): (in ppm) 3.61 (s, 2H), 7.19 (s, 1H), 7.30 (s, 1H).

Embodiment B D

Synthesizing of N-(3-chloro acetyl) L-Ala

According to universal method BF or BG, adopt universal method BD hydrolysis then, with L-L-Ala (Nova Biochem) and 3-chlorobenzene acetic acid (Aldrich) preparation title compound.

Embodiment B 1

N-(phenylacetyl)-D, L-L-Ala isobutyl ester synthetic

According to above universal method BA, with phenyllacetyl chloride (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.23-7.36(m，5H)，6.18(d，1H)，4.58(t，J＝7.3Hz，1H)，3.87(m，2H)，3.57(s，2H)，1.90(m，1H)，1.34(d，J＝7.2Hz，3H)，0.89(d，J＝6.8Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝172.7，170.3，134.5，129.2，128.8，127.2，71.3，48.1，43.4，27.5，18.8，18.3。

C ₁₅H ₂₁NO ₃(MW=263.34); Mass spectrum (MH ⁺=264)).

Embodiment B 2

N-(3-phenyl propionyl)-D, L-L-Ala isobutyl ester synthetic

According to above universal method BA, with 3-phenyl propionyl chloride (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 51-54 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.25(m，2H)，7.19(m，3H)，6.28(d，J＝7.2Hz，1H)，4.58(quint，J＝7.2Hz，1H)，3.89(m，2H)，2.95(t，J＝7.7Hz，2H)，2.50(m，2H)，1.92(m，1H)，1.33(d，J＝7.1Hz，3H)，0.91(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.0，171.5，140.6，128.3，128.1，126.0，71.2，47.8，37.9，31.4，27.5，18.79，18.77，18.3。

C ₁₆H ₂₃NO ₃(MW=277.37); Mass spectrum (MH ⁺278)).

Embodiment B 3

Synthesizing of N-(3-methylpent acyl group)-L-L-Ala isobutyl ester

According to above universal method BB, with 3 methylvaleric acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound oily matter.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.08(d，J＝5.9Hz，1H)，4.62(quint，J＝7.3Hz，1H)，3.92(m，2H)，2.22(m，1H)，1.84-2.00(m，3H)，1.40(d，J＝7.2Hz，3H)，1.35(m，1H)，1.20(m，1H)，0.85-0.96(m，12H)。

¹³C-nmr(CDCl ₃)：δ＝173.3，172.1，71.4，47.9，43.9，32.3，29.38，29.35，27.6，19.10，19.06，18.93，18.91，18.72，18.67，11.3。

C ₁₃H ₂₅NO ₃(MW=243.35); Mass spectrum (MH ⁺244)).

Embodiment B 4

The N-[(4-chloro-phenyl-) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BB, with 4-chlorobenzene acetic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 111-113 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.30(d，J＝8.2Hz，2H)，7.21(d，J＝8.3Hz，2H)，6.18(d，J＝5.5Hz，1H)，4.57(quint，J＝7.2Hz，1H)，3.88(m，2H)，3.53(s，2H)，1.91(m，1H)，1.36(d，J＝7.1Hz，3H)，0.90(d，J＝6.8Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝172.8，169.8，133.1，133.0，130.6，128.9，71.4，48.2，42.6，27.6，18.85，18.82，18.4。

C ₁₅H ₂₀NO ₃Cl (MW=279.78); Mass spectrum (MH ⁺298)).

Embodiment B 5

N-[(3,4-dichlorophenyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BB, with 3,4-fenac (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 81-83 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.90(d，J＝6.8Hz，6H)，1.38(d，J＝7.1Hz，3H)，1.91(m，1H)，3.50(s，2H)，3.90(m，2H)，4.57(quint.，J＝7.1Hz，1H)，6.31(d，J＝4.9Hz，1H)，7.12(m，1H)，7.38(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝18.4，18.8，18.9，27.6，42.2，48.3，71.5，128.6，130.6，131.2，131.3，132.6，134.7，169.2，172.8。

C ₁₅H ₁₉NO ₃Cl ₂(MW=332.23); Mass spectrum (MH ⁺332)).

Embodiment B 6

The N-[(4-aminomethyl phenyl) ethanoyl]-D, L-L-Ala isobutyl ester synthetic

According to above universal method BB, with 4-methylphenyl acetic acid (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 102-104 ℃.By silica gel tlc monitoring reaction (Rf=0.6 launches in 33% ethyl acetate/hexane), by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.90(d，J＝6.7Hz，6H)，1.35(d，J＝7.2Hz，3H)，1.91(m，1H)，2.34(s，3H)，3.55(s，2H)，3.88(m，2H)，4.58(m，1H)，6.05(bd，1H)，7.16(s，4H)。

¹³C-nmr(CDCl ₃)：δ＝18.5，18.85，18.87，21.0，27.6，43.1，48.1，71.3，129.2，129.6，131.3，136.9，170.6，172.8。

C ₁₆H ₂₃NO ₃(MW=277.37); Mass spectrum (MH ⁺278)).

Embodiment B 7

The N-[(3-pyridyl) ethanoyl]-D, L-L-Ala isobutyl ester synthetic

According to above universal method BF, with 3-pyridyl acetic acid hydrochloride (Aldrich) and D, L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 62-64 ℃.By silica gel tlc monitoring reaction (Rf=0.48 launches in 10% ethanol/methylene), by the silica gel column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.40(d，J＝2.8，2H)，7.6(m，1H)，7.16(m，2H)，4.5(quint，J＝7.2，7.2，1H)，3.8(m，2H)，3.48(s，2H)，1.8(m，1H)，1.30(d，J＝7.2，3H)，0.81(d，J＝6.7，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.4，170.1，150.6，148.8，137.4，131.4，124.1，71.9，48.9，40.6，28.1，19.5，19.4，18.6。

C ₁₄H ₂₀N ₂O ₃(MW=264); Mass spectrum (MH ⁺265)).

Embodiment B 8

The N-[(1-naphthyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BB, with 1-naphthylacetic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 69-73 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.83(m，6H)，1.25(d，J＝7.1Hz，3H)，1.81(m，1H)，3.79(m，2H)，4.04(2s，2H)，4.57(quint.，J＝7.3Hz，1H)，5.99(d，J＝7.1Hz，1H)，7.44(m，2H)，7.53(m，2H)，7.85(m，2H)，7.98(m，1H)。

¹³C-nmr(CDCl ₃)：δ＝18.2，18.81，18.83，27.5，41.5，48.2，71.3，123.7，125.6，126.1，126.6，128.2，128.5，128.7，130.7，132.0，133.9，170.3，172.5。

C ₁₉H ₂₃NO ₃(MW=313.40); Mass spectrum (MH ⁺314)).

Embodiment B 9

The N-[(2-naphthyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BB, with 2-naphthylacetic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 128-129 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.86(m，6H)，1.35(d，J＝7.1Hz，3H)，1.78(m，1H)，3.76(s，2H)，3.87(m，2H)，4.62(quint.，J＝7.2Hz，1H)，6.13(d，J＝7.1Hz，1H)，7.41(m，1H)，7.48(m，2H)，7.74(s，1H)，7.83(m，3H)。

¹³C-nmr(CDCl ₃)：δ＝18.4，18.82，18.85，27.6，43.7，48.2，71.4，125.9，126.3，127.2，127.6，127.7，128.2，128.7，132.0，132.5，133.5，170.3，172.8。

C ₁₉H ₂₃NO ₃(MW=313.40); Mass spectrum (MH ⁺314)).

Embodiment B 10

Synthesizing of N-(4-phenyl butyryl radicals)-L-L-Ala isobutyl ester

According to above universal method BB, with 4-phenylbutyric acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound oily matter.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.92(d，J＝6.7Hz，6H)，1.38(d，J＝7.1Hz，3H)，1.96(m，3H)，2.21(t，J＝7.1Hz，2H)，2.64(t，J＝7.3Hz，2H)，3.90(m，2H)，4.59(quint.，J＝7.2Hz，1H)，6.31(d，1H)，7.16(m，3H)，7.24(m，2H)。

¹³C-nmr(CDCl ₃)：δ＝18.3，18.75，18.78，26.8，27.5，34.9，35.3，47.8，71.2，125.7，128.2，128.3，141.3，172.1，173.0。

C ₁₇H ₂₅NO ₃(MW=291.39); Mass spectrum (MH ⁺292)).

Embodiment B 11

Synthesizing of N-(5-phenyl pentanoyl)-L-L-Ala isobutyl ester

According to above universal method BB, with 5-phenylpentanoic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound oily matter.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.23(m，2H)，7.17(m?3H)，6.30(d，1H)，4.59(quint.，J＝7.3Hz，1H)，3.91(m，2H)，2.61(t，J＝7.2Hz，2H)，2.22(t，J＝7.2Hz，2H)，1.93(m，1H)，1.66(m，4H)，1.38(d，J＝7.2Hz，3H)，0.92(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.1，172.3，142.0，128.2，128.1，125.6，71.2，47.8，36.1，35.5，30.8，27.5，25.0，18.80，18.77，18.4。

C ₁₈H ₂₇NO ₃(MW=304.39); Mass spectrum (MH ⁺306)).

Embodiment B 12

The N-[(4-pyridyl) ethanoyl]-D, L-L-Ala isobutyl ester synthetic

According to above universal method BF, with 4-pyridine acetic acid hydrochloride (Aldrich) with (D, L)-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) prepares the title compound solid, its fusing point is 64-66 ℃.By silica gel tlc monitoring reaction (Rf=0.43 launches in 10% ethanol/methylene), and by the silica gel column chromatography purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.51(dd，J＝1.6，2.8，1.6，2H)，7.23(dd，J＝4.3，1.6，4.4，2H)，6.71(d，J＝6.8，1H)，4.56(quint，J＝7.3，7.2，1H)，3.88(m，2H)，3.53(s，2H)，1.89(m，1H)，1.36(d，J＝7.2，3H)，0.88(d，J＝6.7，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.5，169.3，150.5，144.4，125.1，72.1，48.9，43.0，28.2，19.5，19.5，18.9。

C ₁₄H ₂₀N ₂O ₃(MW=264); Mass spectrum (MH ⁺265)).

Embodiment B 13

Synthesizing of N-(phenylacetyl)-L-L-Ala isobutyl ester

According to above universal method BB, with phenyllacetyl chloride (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 45-47 ℃.By silica gel tlc monitoring reaction, by using extracted with diethyl ether, then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.24-7.39(m，5H)，6.14(d，1H)，4.58(t，J＝7.3Hz，1H)，3.88(m，2H)，3.58(s，2H)，1.90(m，1H)，1.35(d，J＝7.2HZ，3H)，0.89(d，J＝6.7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝172.8，170.4，134.5，129.3，128.9，127.2，71.3，48.1，43.5，27.5，18.9，18.8，18.4。

C ₁₅H ₂₁NO ₃(MW=263.34); Mass spectrum (MH ⁺264)).

Embodiment B 14

2-[(3,4-dichlorophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3,4-fenac (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.36(m，3H)，6.03(bd，1H)，4.54(m，1H)，3.87(m，2H)，3.49(s，2H)，1.93(m，2H)，1.72(m，1H)，0.88(d，6H)，0.80(t，3H)。

Embodiment B 15

The 2-[(3-p-methoxy-phenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-methoxyphenylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.75(m，4H)，5.93(bd，1H)，4.51(m，1H)，3.83(m，2H)，3.75(s，2H)，3.52(s，2H)，1.82(m，2H)，1.60(m，1H)，0.84(d，6H)，0.74(t，3H)。

C ₁₇H ₂₅NO ₄(MW=307.39); Mass spectrum (MH ⁺309)).

Embodiment B 16

The 2-[(4-nitrophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 4-nitrophenyl-acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.16(d，2H)，7.44(d，2H)，6.04(bd，1H)，4.55(m，1H)，3.86(m，2H)，3.66(s，2H)，1.86(m，2H)，1.67(m，1H)，0.85(d，6H)，0.81(t，3H).

C ₁₆H ₂₂N ₂O ₅(MW=322.36); Mass spectrum (MH ⁺323)).

Embodiment B 17

2-[(3,4-methylenedioxyphenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3,4-(methylene-dioxy) toluylic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.72(m，3H)，5.92(bd，1H)，4.54(m，1H)，3.86(m，2H)，3.66(s，2H)，1.86(m，2H)，1.66(m，1H)，0.89(d，6H)，0.79(t，3H)。

Embodiment B 18

The 2-[(thiene-3-yl-) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-thiophene acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.37(m，1H)，7.16(m，1H)，7.04(m，1H)，6.05(bd，1H)，4.57(m，1H)，3.66(s，2H)，1.93(m，2H)，1.67(m，1H)，0.91(d，6H)，0.86(t，3H)。

Embodiment B 19

The 2-[(4-chloro-phenyl-) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 4-chlorobenzene acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.22(m，2H)，7.11(m，2H)，5.80(m，1H)，4.44(m，1H)，3.78(m，2H)，3.43(s，2H)，1.77(m，2H)，1.56(m，1H)，0.83(d，6H)，0.71(t，3H)。

Embodiment B 20

The 2-[(3-nitrophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-nitrophenyl-acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.15(m，2H)，7.65(m，1H)，6.08(m，1H)，4.46(m，1H)，3.92(m，2H)，3.68(s，2H)，1.91(m，2H)，1.75(m，1H)，0.98(d，6H)，0.71(t，3H)。

Embodiment B 21

The 2-[(2-hydroxy phenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2-Hydroxyphenyl Acetic Acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.14(m，1H).7.01(m，1H)，6.93(m，1H)，6.79(m，1H)，6.46(m，1H)，4.51(m，1H)，3.87(m，2H)，3.57(s，2H)，2.01(m，2H)，1.75(m，1H)，0.89(d，6H)，0.85(t，3H)。

Embodiment B 22

The 2-[(2-naphthyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2-naphthylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.83(m，7H)，5.95(m，1H)，4.58(m，1H)，3.84(m，2H)，3.75(s，2H)，1.89(m，2H)，1.63(m，1H)，0.91(d，6H)，0.81(t，3H)。

C ₂₀H ₂₅NO ₃(MW=327.42); Mass spectrum (MH ⁺328)).

Embodiment B 23

2-[(2,4-dichlorophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2,4 dichloro benzene acetate (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.49(m，1H)，7.22(m，2H)，5.98(m，1H)，4.52(m，1H)，3.86(m，2H)，3.61(s，2H)，1.84(m，2H)，1.62(m，1H)，0.87(d，6H)，0.80(t，3H)。

Embodiment B 24

The 2-[(4-bromophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 4-bromo-acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.43(d，2H)，7.19(d，2H)，5.85(m，1H)，4.51(m，1H)，3.81(m，2H)，3.47(s，2H)，1.84(m，2H)，1.61(m，1H)，0.84(d，6H)，0.76(t，3H)。

C ₁₆H ₂₂NO ₃Br (MW=356.26); Mass spectrum (MH ⁺358)).

Embodiment B 25

The 2-[(3-chloro-phenyl-) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-chlorobenzene acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.25(m，3H)，7.12(m，1H)，5.80(m，1H)，4.52(m，1H)，3.86(m，2H)，3.50(s，2H)，1.87(m，2H)，1.67(m，1H)，0.88(d，6H)，0.77(t，3H)。

C ₁₆H ₂₂NO ₃Cl (MW=311.81); Mass spectrum (MH ⁺313)).

Embodiment B 26

The 2-[(3-fluorophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-fluorophenylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.31(m，1H)，7.01(m，3H)，5.95(m，1H)，4.54(m，1H)，3.84(m，2H)，3.54(s，2H)，1.88(m，2H)，1.65(m，1H)，0.87(d，6H)，0.81(t，3H)。

C ₁₆H ₂₂NO ₃F (MW=295.35); Mass spectrum (MH ⁺296)).

Embodiment B 27

2-[(benzothiazole-4-yl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 4-benzothiazole-4-guanidine-acetic acid (Chemservice) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.82(m，1H)，7.51-7.21(m，4H)，5.84(m，1H)，4.51(m，1H)，3.90(s，2H)，3.79(m，2H)，1.78(m，2H)，1.58(m，1H)，0.80(d，6H)，0.66(t，3H)。

Embodiment B 28

The 2-[(2-aminomethyl phenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2-methylphenyl acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.18(m，4H)，5.79(m，1H)，4.54(m，1H)，3.85(m，2H)，3.59(s，2H)，3.29(s，3H)，1.81(m，2H)，1.59(m，1H)，0.87(d，6H)，0.77(t，3H)。

C ₁₇H ₂₅NO ₃(MW=291.39); Mass spectrum (MH ⁺291)).

Embodiment B 29

The 2-[(2-fluorophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2-fluorophenylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.28(m，1H)，7.09(m，3H)，6.03(m，1H)，4.54(m，1H)，3.87(m，2H)，3.57(s，2H)，1.89(m，2H)，1.64(m，1H)，0.88(d，6H)，0.80(t，3H)。

Embodiment B 30

The 2-[(4-fluorophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 4-fluorophenylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.20(m，2H)，6.97(m，2H)，5.87(m，1H)，4.492(m，1H)，3.83(m，2H)，3.48(s，2H)，1.86(m，2H)，1.60(m，1H)，0.87(d，6H)，0.78(t，3H)。

C ₁₆H ₂₂NO ₃F (MW=295.35); Mass spectrum (MH ⁺296)).

Embodiment B 31

The 2-[(3-bromophenyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-bromo-acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.45(m，2H)，7.23(m，2H)，5.95(m，1H)，4.55(m，1H)，3.84(m，2H)，3.55(s，2H)，1.89(m，2H)，1.68(m，1H).0.91(d，6H)，0.81(t，3H)。

C ₁₆H ₂₂NO ₃Br (MW=356.26); Mass spectrum (MH ⁺357)).

Embodiment B 32

The 2-[(3-trifluoromethyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 3-trifluoromethyl phenylacetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.52(m，1H)，7.47(m，2H)，6.01(m，1H)，4.56(m，1H)，3.86(m，2H)，3.61(s，2H)，1.84(m，2H)，1.62(m，1H)，0.87(d，6H)，0.80(t，3H)。

C ₁₇H ₂₂NO ₃F ₃(MW=345.36); Mass spectrum (MH ⁺345)).

Embodiment B 33

The 2-[(2-thienyl) kharophen] isobutyl butyrate synthetic

According to above universal method BI, with 2-thiophene acetic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.89(m，3H)，6.07(bd，1H)，4.50(m，1H)，3.82(m，2H)，3.71(s，2H)，1.85(m，2H)，1.62(m，1H)，0.8?1(d，6H)，0.75(t，3H)。

C ₁₄H ₂₁NO ₃S (MW=283.39); Mass spectrum (MH ⁺284)).

Embodiment B 34

Synthesizing of 2-(phenyl kharophen) isobutyl butyrate

According to above universal method BH, with toluylic acid (Aldrich) and 2-aminobutyric acid isobutyl ester (according to above universal method BJ preparation) preparation title compound.By silica gel tlc monitoring reaction, and with 9: 1 toluene: EtOAc as eluent through chromatography purification.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.17-7.28(m，5H)，6.23(bd，1H)，4.51(m，1H)，3.86(m，2H)，3.54(s，2H)，1.87(m，2H)，1.62(m，1H)，0.87(d，6H)，0.78(t，3H)。

C ₁₆H ₂₃NO ₃(MW=277.36); Mass spectrum (MH ⁺277)).

Embodiment B 35

The preparation of synthesis step A.N-(phenylacetyl) Xie Ansuan of N-(phenyl acetyl) Xie Ansuan 2-methyl butyl ester

Dropwise 5 .3ml (40mmol) phenyllacetyl chloride (Aldrich) in being cooled to 0 ℃ the stirred solution of 50ml (100mmol) 2N NaOH of 5.15g (44mmol) Xie Ansuan (Bachem).The colorless oil precipitation.Allow the reaction mixture temperature to room temperature, and stirred 18 hours,, be acidified to pH 2-3 with aqueous hydrochloric acid with the washing of 50ml ether.Leach the white precipitate of formation, water thoroughly washs, and then with the ether washing, obtains the title compound of 7.1g (30mmol, 69%).

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝12.63(s，1H)，8.25(d，J＝8.6Hz，1H)，7.27(m，5H)，4.15(m，1H)，3.56(d，J＝13.8Hz，1H)，3.47(d，J＝13.8Hz，1H)，2.05(m，1H)，0.87(d，J＝6.8Hz，3H)，0.84(d，J＝6.8Hz，3)。

¹³C-nmr(DMSO-d ₆)：δ＝173.2，170.4，136.6，129.0，128.2，126.3，57.1，41.9，30.0，19.2，18.0。

C ₁₃H ₁₇NO ₃(MW=235.29); Mass spectrum (MH ⁺=236)).Synthesizing of step B.N-(phenylacetyl) Xie Ansuan 2-methyl butyl ester

According to above universal method BC, with the title compound of the N-for preparing in the steps A (phenylacetyl) Xie Ansuan and 2-methyl fourth-1-alcohol (Aldrich) preparation as non-enantiomer mixture.By silica gel tlc monitoring reaction, and as filtration purifying as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.25-7.40(m，5H)，5.95(d，1H)，4.56(m，1H)，3.84-4.00(m，2H)，3.61(s，2H)，210(m，1H)，1.68(m，1H)，1.38(m，1H)，1.15(m，1H)，0.82-0.94(m，9H)，0.76(d，3H)。

¹³C-nmr(CDCl ₃)：δ＝171.84，171.81，170.7，134.6，129.31，129.27，128.9，127.3，69.8，57.0，43.7，33.9，31.3，25.9，25.8，18.9，17.4，16.34，16.27，11.12，11.07。

C ₁₈H ₂₇NO ₃(MW=305.42); Mass spectrum (MH306)).

Embodiment B 36

Synthesizing of N-(phenylacetyl)-L-methionine(Met) isobutyl ester

(0.129g, 0.869mmol) (Aldrich) is absorbed in the diox (5.0ml), handles with saturated sodium bicarbonate aqueous solution (5.0ml), uses phenyllacetyl chloride (Aldrich) (0.114ml.0.822mmol) to handle then with the L-methionine(Met).After stirring 17 hours under the room temperature, mixture dilutes with ethyl acetate, separates each layer, with 5N HCl water layer is acidified to pH 2.Crude product is extracted in the ethyl acetate, and through dried over sodium sulfate, vacuum-drying is used without being further purified.

(0.1285g 0.447mmol) is dissolved in 3.0ml diox and the isopropylcarbinol (0.2ml), and (0.094g 0.492mmol) handles with catalysis DMAP (0.015g) with EDC with N-phenylacetyl-L-methionine(Met)., after 17 hours the mixture reduction vaporization to oily matter, is diluted resistates in ethyl acetate in 23 ℃ of stirrings, with 0.1N HCl and saturated sodium bicarbonate aqueous solution washing.Adopt 98: 2 chloroform/methanol to separate through silica gel column chromatography, obtain purified product as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.4-7.23(m，5H)，6.14(bd，1H)，4.70(m，1H)，3.89(d，2H)，3.62(s，2H)，2.43(m，2H)，2.12(m，1H)，1.93(m，2H)，0.94(d，6H)。

C ₁₇H ₂₅NO ₃S (MW=323.17); Mass spectrum (M ⁺323)).

Embodiment B 37

Synthesizing of N-(phenylacetyl)-L-leucine isobutyl ester

(0.114g, 0.869mmol) (Aldrich) is absorbed in the diox (5.0ml), handles with saturated sodium bicarbonate aqueous solution (5.0ml), uses phenyllacetyl chloride (Aldrich) (0.114ml.0.822mmol) to handle then with the L-leucine.After stirring 17 hours under the room temperature, mixture dilutes with ethyl acetate, separates each layer, with 5N HCl water layer is acidified to pH 2.Crude product is extracted in the ethyl acetate, and through dried over sodium sulfate, vacuum-drying is used without being further purified.

(0.0081g 0.038mmol) is dissolved in 2.0ml chloroform (no ethanol) and the isopropylcarbinol (0.055ml), handles with P-EPC (100mg, 0.87 milliequivalent) with N-phenylacetyl-L-leucine.With mixture rotation 4 days, filter by tampon, to oily matter, the purity of described oily matter is enough to be used in test with filtrate evaporated under reduced pressure.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.22(m，5H)，5.57(d，1H)，4.35(m，1H)，3.35(m，3H)，1.35(m，4H)，0.68(m，9H)。

C ₁₈H ₂₇NO ₃(MW=305.40); Mass spectrum (M ⁺305)).

Embodiment B 38

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 3-methyl but-2-ene ester synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and 3-methyl but-2-ene-1-alcohol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 30% EtOAc/ hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.39-7.16(m，4H)，6.06(bd，1H)，5.38-5.29(m，1H)，4.63(d，J＝9Hz，2H)，3.56(s，2H)，1.79(s，3H)，1.7(s，3H)，1.39(d，J＝9Hz，3H)。

Embodiment B 39

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala cyclopropyl methyl esters synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and cyclopropyl-carbinol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.2-7.1(m，4H)，6.09(bs，1H)，4.6(dq，J＝9Hz，1H)，3.96(dd，J＝9Hz，2H)，3.59(s，2H)，1.2(d，J＝9Hz，3H)，1.2-1.0(m，1H)，0.603-0.503(m，2H)，0.300-0.203(m，2H)。

Embodiment B 40

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 2-thienyl methyl esters synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and 2-thiophen(e)alcohol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.37-6.97(m，7H)，5.97(q，J＝14Hz，2H)，4.6(dq，J＝9Hz，1H)，3.76(s，2H)，1.38(d，J＝9Hz，3H)。

Embodiment B 41

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala (1-methyl cyclopropyl) methyl esters synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and (1-methyl cyclopropyl) methyl alcohol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.6(bd，J＝9Hz，1H)，3.86(q，J＝14Hz，2H)，3.4(s，2H)，2.29(q，J＝9Hz，1H)，1.3(d，J＝9Hz，3H)，1.03(s，3H)，0.5-0.4(m，2H)，0.4-0.28(m，2H)。

Embodiment B 42

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 3-thienyl methyl esters synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and 3-thiophen(e)alcohol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.03(bd，J＝9Hz，1H)，7.56-7.5(m，1H)，7.47(bs，1H)，7.4-7.17(m，4H)，7.06(d，J＝9Hz，1H)，5.1(s，2H)，4.3(dq，1H)，1.3(d，J＝9Hz，3H)。

Embodiment B 43

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 2-methyl ring pentyl ester synthetic

According to above universal method BC, with N-(3-chloro acetyl) L-Ala (deriving from above Embodiment B D) and 2-methylcyclopentanol (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.39-7.16(m，4H)，6.3(bd，1H)，4.79-4.7(m，1H)，4.6-4.25(m，J＝9Hz，1H)，3.577(s，2H)，2.09-1.8(m，2H)，1.74-1.6(m，2H)，1.39(dd，J＝9Hz，3H)，1.2(dt，J＝9Hz，1H)，0.979(dd，J＝9Hz，2H)。

C ₁₇H ₂₂NO ₃Cl (MW=323.82, mass spectrum (MH ⁺323).

Embodiment B 44

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 2-methyl-prop-2-alkene ester synthetic

According to above universal method BC, with N-(3-chloro acetyl L-Ala (deriving from above Embodiment B D) and 2-methyl-prop-2-alkene-1-alcohol (Aldrich), preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.39-7.16(m，4H)，6.03(bs，1H)，4.77(s，2H)，4.7-4.29(m，3H)，2.59(s，2H)，1.73(s，3H)，1.43(d，J＝9Hz，3H)。

C ₁₅H ₁₈NO ₃Cl (MW=295.76, mass spectrum (MH ⁺295)).

Embodiment B 45

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala hexamethylene-2-alkene ester synthetic

According to above universal method BC, with N-(3-chloro acetyl) L-Ala (deriving from above Embodiment B D) and hexamethylene-2-alkene-1-alcohol (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction, with 3: 7 EtOAc: hexane as eluent through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.6(bd，J＝9Hz，1H)，7.4-7.2(m，4H)，6.0-5.8(m，1H)，5.7-5.5(m，1H)，5.1(bs，1H)，4.13-4.29(m，1H)，3.5(s，2H)，2.1-1.9(m，2H)，1.8-1.69(m，1H)，1.69-1.49(m，4H)，1.3(dd，J＝9Hz，3H)。

C ₁₇H ₂₀NO ₃Cl (MW=321.8, mass spectrum (MH ⁺321.2)).

Embodiment B 46

N-[(2-Ben base benzoxazole-5-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 5-(2-Ben base benzoxazole)-guanidine-acetic acid (CAS#62143-69-5) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.24(m，3H)，7.68(m，1H)，7.51(m，5H)，6.04(m，1H)，4.58(m，1H)，3.85(m，2H)，3.68(s，2H)，1.9(m，1H)，1.35(d，3H)，0.87(d，6H)。

C ₂₂H ₂₄N ₂O ₄(MW=380, mass spectrum (MH ⁺381)).

Embodiment B 47

N-[(3-thiotolene base) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 3 methyl thiophene guanidine-acetic acid (CAS# 18698-73-2) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.14(m，2H)，7.01(m，1H)，4.56(m，1H)，3.88(m，2H)，3.54(s，2H)，2.46(s，3H)，1.89(m，1H)，1.35(d，3H)，0.85(d，6H)。

C ₁₆H ₂₃NO ₃S (MW=309, mass spectrum (MH ⁺310)).

Embodiment B 48

The N-4-[(2-furyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 2-furyl acetate (CAS# 2745-26-8) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.36(m，1H)，6.34(m，1H)，6.21(m，1H)，4.56(m，1H)，3.91(m，2H)，3.61(s，2H)，1.92(m，1H)，1.38(d，3H)，0.89(d，6H)。

C ₁₃H ₁₉NO ₄(MW=253, mass spectrum (MH ⁺254)).

Embodiment B 49

N-[(cumarone-2-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with cumarone-2-guanidine-acetic acid (Maybridge) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.51(m，1H)，7.44(m，1H)，7.25(m，2H)，6.67(s，1H)，4.60(m，1H)，3.87(m，2H)，3.77(s，2H)，1.88(m，1H)，1.38(d，3H)，0.87(d，6H)。

C ₁₇H ₂₁NO ₄(MW=303, mass spectrum (MH ⁺304)).

Embodiment B 50

N-[(thionaphthene-3-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with benzo-thiophene-3-guanidine-acetic acid (Lancaster) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.89(m，1H)，7.76(m，1H)，7.38(m，3H)，6.07(m，1H)，4.57(m，1H)，3.92(m，2H)，3.82(s，4H)，1.84(m，1H)，1.32(d，3H)，0.85(d，6H)。

C ₁₇H ₂₁NO ₃S (MW=319, mass spectrum (MH ⁺320)).

Embodiment B 51

N-[(2-chloro-5-thienyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 5-chloro-2-thienyl) acetate (CAS# 13669-19-7) and L-Ala isobutyl ester (according to above universal method BJ preparation), the preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.77(m，1H)，6.68(d，1H)，6.31(bm，1H)，4.59(m，1H)，3.91(m，2H)，3.38(s，2H)，1.90(m，1H)，1.39(d，3H)，0.89(d，6H)。

C ₁₃H ₁₈NO ₃SCl (MW=303, mass spectrum (MH ⁺303)).

Embodiment B 52

N-[(3-methyl-isoxazole-5-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with (3-methyl-isoxazole-5-bases) acetate (CAS#19668-85-0) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.07(s，2H)，4.56(m，1H)，3.92(m，2H)，3.68(s，2H)，2.29(s，3H)，1.94(m，1H)，1.89(d，3H)，0.91(d，6H)。

C ₁₃H ₂₀N ₂O ₄(MW=268, mass spectrum (MH ⁺269)).

Embodiment B 53

N-[(2-thiophenyl thienyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with (2-thiophenyl thienyl) acetate and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.21-7.11(m，6H)，6.92(d，1H)，4.56(m，1H)，3.87(m，2H)，3.72(s，2H)，1.94(m，1H)，1.38(d，3H)，0.89(d，6H)。

C ₁₉H ₂₃NO ₃S ₂(MW=377, mass spectrum (MH ⁺378)).

Embodiment B 54

N-[(6-anisole thiophthene-2-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with (6-methoxyl group benzo-thiophene-2-yl) acetate and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.59(d，1H)，7.33(d，1H)，7.16(s，1H)，7.03(dd，1H)，4.56(m，1H)，3.87(s，3H)，3.84(m，2H)，3.76(s，2H)，1.85(m，1H)，1.30(d，3H)，0.86(d，6H)。

C ₁₈H ₂₃NO ₄S (MW=349, mass spectrum (MH ⁺350)).

Embodiment B 55

N-[(3-phenyl-1,2,4-thiadiazoles-5-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with (3-phenyl-1,2,4-thiadiazoles-5-yl) acetate (CAS#90771-06-5) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.47(m，5H)，4.66(m，1H)，4.16(s，2H)，3.91(m，2H)，1.93(m，1H)，1.48(d，3H)，0.93(d，6H)。

C ₁₇H ₂₁N ₃O ₃S (MW=347, mass spectrum (MH ⁺348)).

Embodiment B 56

N-[(2-Ben Ji oxazole-4-yl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with (2-Ben Ji oxazole-4-yl) acetate (CAS# 22086-89-1) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

Embodiment B 57

The N-[(3-aminomethyl phenyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 3-methylphenyl acetic acid (Aldrich) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.21(m，1H)，7.07(m，3H)，4.54(m，1H)，3.83(m，2H)，3.52(s，2H)，2.35(s，3H)，1.87(m，1H)，1.32(d，3H)，0.88(d，6H)。

C ₁₆H ₂₃NO ₃(MW=277, mass spectrum (MH ⁺278)).

Embodiment B 58

N-[(2,5-difluorophenyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 2,5-difluorophenyl acetic acid (Aldrich) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.08-6.94(m，3H)，4.57(m，1H)，3.91(m，2H)，3.56(s，2H)，1.92(m，1H)，1.41(d，3H)，0.91(d，6H)。

C ₁₅H ₁₉NO ₃F ₂(MW=299, mass spectrum (MH ⁺300)).

Embodiment B 59

N-[(3,5-difluorophenyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 3,5-difluorophenyl acetic acid (Aldrich) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝6.81(m，2H)，6.74(m，1H)，6.06(m，1H)，4.57(m，1H)，3.92(m，2H)，3.51(s，2H)，1.94(m，1H)，1.36(d，3H)，0.87(d，6H)。

C ₁₅H ₁₉NO ₃F ₂(MW=299, mass spectrum (MH ⁺300)).

Embodiment B 60

The N-[(3-thienyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 3-thiophene acetic acid (Aldrich) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.33(m，1H)，7.14(m，1H)，7.01(m，1H)，6.09(m，1H)，4.58(m，1H)，3.88(m，2H)，3.60(s，2H)，1.91(m，1H)，1.37(d，3H)，0.92(d，6H).

Specific rotation: [α] ₂₃-52 (c1 is MeOH) in 589nm.

C ₁₃H ₁₉NO ₃S (MW=269, mass spectrum (MH ⁺269)).

Embodiment B 61

The N-[(4-aminomethyl phenyl) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BI, with 4-methylphenyl acetic acid (Aldrich) and L-L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction, and carry out purifying as filtration as described in the universal method.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.11(s，4H)，5.93(m，1H)，4.58(m，1H)，3.88(m，2H)，3.54(s，2H)，2.33(s，3H)，1.89(m，1H)，1.32(d，3H)，0.89(d，6H)。

C ₁₆H ₂₃NO ₃(MW=277.35, mass spectrum (MH ⁺278)).

Embodiment B 62

The N-[(phenylacetyl) ethanoyl]-L-L-Ala S-1-(methoxycarbonyl) isobutyl ester synthetic

According to above universal method BK, replace described amino acid with (S)-(+)-2-hydroxy-2-methyl butyric acid (Aldrich), preparation (S)-(+)-2-hydroxy-2-methyl methyl-butyrate.

Adopt universal method BE then,, obtain carbonyl benzyloxy-L-L-Ala (S)-1-(methoxycarbonyl) isobutyl ester (S)-(+)-2-hydroxy-2-methyl methyl-butyrate and carbonyl benzyloxy-L-L-Ala (Aldrich) coupling.

Then carbonyl benzyloxy-L-L-Ala (S)-1-(methoxycarbonyl) isobutyl ester (1.0g) is dissolved in the 20ml methyl alcohol, adds 6N HCl (0.5ml) and 10% palladium carbon (0.1g).On the Parr device,, filter through Celite pad then the hydrogenation 5 hours under room temperature, 40psi hydrogen of this reaction mixture.Concentrating under reduced pressure filtrate obtains L-L-Ala S-1-(methoxycarbonyl) isobutyl ester hydrochloride (yield 98%).

Adopt universal method BG then,, obtain title compound L-L-Ala S-1-(methoxycarbonyl) isobutyl ester hydrochloride and toluylic acid coupling.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.35-7.20(m，5H)，6.22(bd，1H)，4，83(d，1H)，4.65(p，1H)，3.68(s，3H)，3.55(s，2H)，2.21(m，1H)，1.40(d，3H)，0.97(d，3H)，0.93(d，3H)。

¹³C-nmr(CDCl ₃)：δ＝173.25，171.18，170.22，135.11，129.94，129.50，127.88，52.67，48.49，43.98，30.53，19.21，18.75，17.58。

Embodiment B 63

The N-[(3-nitrophenyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BH, with 3-nitrophenyl-acetic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B), the preparation title compound.By silica gel tlc monitoring reaction, and recrystallization carries out purifying from Butyryl Chloride.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.17(m，2H)，7.68(d，1H)，7.52(t，1H)，6.18(m，1H)，4.48(m，1H)，3.94(m，2H)，3.67(s，2H)，1.93(m，1H)，1.42(d，3H)，0.91(d，3H)。

Specific rotation: [α] ₂₀-49 (c5, MeOH).

Embodiment B 64

N-[(3,5-difluorophenyl) ethanoyl] alanine ethyl ester synthetic

According to above universal method BG, with 3,5-difluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), preparation title compound solid, fusing point is 93-95 ℃.By silica gel tlc monitoring reaction (Rf=0.8 launches in ethyl acetate),, use ethyl acetate as the eluent purifying, then recrystallization from 1-chlorobutane through silica gel column chromatography.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.30(d，3H)；3.52(s，2H)。

C ₁₃H ₁₅NO ₃F ₂(MW=271.26, mass spectrum (MH ⁺271)).

Embodiment B 65

The N-[(3-nitrophenyl) ethanoyl] methionine(Met) ethyl ester synthetic

According to above universal method BG, with 3-nitrophenyl-acetic acid (Aldrich) and methionine(Met) carbethoxy hydrochloride (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction, recrystallization carries out purifying from chlorobutane.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.18(s，1H)，8.15(d，1H)，7.66(d，1H)，7.48(t，1H)，6.30(m，1H)，4.67(m，1H)，4.21(t，2H)，3.67(s，2H)，2.47(t，2H)，2.12(m，2H)，2.08(s，3H)，1.27(t，3H)。

Specific rotation: [α] ₂₃-30 (c5, MeOH).

Embodiment B 66

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala isobutyl ester synthetic

According to above universal method BG, with 3-chlorobenzene acetic acid (Aldrich) and L-Ala isobutyl ester (according to above universal method BJ preparation), preparation title compound.By silica gel tlc monitoring reaction.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.29(m，3H)，7.1?8(m，1H)，6.0(m，1H)，4.56(m，1H)，3.89(m，2H)，3.53(s，2H)，1.91(m，1H)，1.39(d，3H)，0.91(d，3H)。

Specific rotation: [α] ₂₃-45 (c5, MeOH).

C ₁₅H ₂₀NO ₃Cl (MW=297.78, mass spectrum (MH ⁺297)).

Embodiment B 67

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 2-(N, N-dimethylamino) ethyl ester synthetic

According to above universal method BC, with N-(3-chloro acetyl) L-Ala (deriving from above Embodiment B D) and 2-(N, N-dimethylamino) ethanol (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction, adopt 0.1: 2: 0.79 ammonium hydroxide: ethanol: chloroform carries out purifying as eluent through liquid chromatography (LC).

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.37(s，1H)，7.33-7.2(m，3H)，4.675-4.6(m，1H)，4.5-4.37(m，1H)，4.25-4.13(m，1H)，3.6(d，J＝7Hz，2H)，2.86(bs，2H)，2.3(s，6H)，1.23(d，J＝9Hz，3H)。

C ₁₅H ₂₁N ₂O ₃Cl (MW=313.799, mass spectrum (MH ⁺313)).

Embodiment B 68

2-[(3,5-dichlorophenyl) kharophen] methyl caproate synthetic

According to above universal method BF, with 3,5-fenac (deriving from above Embodiment B C) and L-nor-leucine methyl ester hydrochloride (Bachem) preparation title compound solid, its fusing point is 77-78 ℃.By silica gel tlc monitoring reaction (Rf=0.70 launches in the 40%EtOAc/ hexane), and adopt the 40%EtOAc/ hexane, through quick silica gel column chromatography purifying as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.20(s)，7.18(s)，6.6(m)，4.55(m)，3.7(s)，3.5(s)，3.4(s)，2.0(s)，1.8(m)，1.6(m)，1.2(m)，0.8(t)。

¹³C-nmr(CDCl ₃)：δ＝173.54，169.67，138.43，135.72，128.33，128.07，78.04，77.62，77.19，53.04，52.90，43.14，32.57，27.87，22.81，14.41。

Embodiment B 69

N-[(3,5-dichlorophenyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BF, with 3,5-fenac (deriving from above Embodiment B C) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 115-116 ℃.By silica gel tlc monitoring reaction (Rf=0.40 launches in 3% ethanol/methylene), and adopt 3% ethanol/methylene, through quick silica gel column chromatography purifying as eluent.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.27(d，J＝2Hz，1H)，7.19(s，2H)，6.22(d，J＝6Hz，1H)，4.59(quint.，J＝7Hz，1H)，3.9(q，J＝4Hz，2H)3.5(s，2H)，1.9(m，1H)，1.4(d，J＝7Hz，3H)，0.91(d，J＝7Hz，6H)。

¹³C-nmr(CDCl ₃)：δ＝173.45，169.37，138.31，135.75，128.39，128.11，78.04，77.61，77.19，72.19，54.03，48.97，43.12，28.24，19.52，19.49，19.09。

C ₁₅H ₁₉NO ₃Cl ₂(MW=331.9, mass spectrum (MH ⁺332)).

Embodiment B 70

Synthesizing of N-(cyclohexyl ethanoyl)-L-L-Ala isobutyl ester

According to above universal method BB, with cyclohexyl acetic acid (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 92-93 ℃.By silica gel tlc monitoring reaction (Rf=0.39 is at 1: 3 EtOAc: launch in the hexane), and with extracted with diethyl ether then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.93(d，J＝6.7Hz，6H)，0.85-1.01(m，2H)，1.05-1.35(m，3H)，1.40(d，J＝7.1Hz，3H)，1.60-1.85(m，6H)，1.95(m，1H)，2.06(d，J＝7.0Hz，2H)，3.92(m，2H)，4.61(m，1H)，6.08(bd，1H)。

¹³C-nmr(CDCl ₃)：δ＝18.7，18.9，26.0，26.1，27.6，33.0，35.3，44.6，47.9，71.4，171.8，173.3。

C ₁₅H ₂₇NO ₃(MW=269.39, mass spectrum (MH ⁺270)).

Embodiment B 71

Synthesizing of N-(cyclopentyl ethanoyl)-L-L-Ala isobutyl ester

According to above universal method BB, with NSC 60134 (Aldrich) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 62-64 ℃.By silica gel tlc monitoring reaction (Rf=0.37 is at 1: 3 EtOAc: launch in the hexane), and with extracted with diethyl ether then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.87(d，J＝6.8Hz，6H)，1.01-1.17(m，2H)，1.34(d，J＝7.2Hz，3H)，1.40-1.62(m，4H)，1.70-1.83(m，2H)，1.89(m，1H)，2.15(m，3H)，3.86(m，2H)，4.55(m，1H)，6.30(d，J＝7.1Hz，1H)。

¹³C-nmr (CDCl ₃): δ=18.4,18.78,18.80,24.8 (very high), 27.5,32.27,32.32,36.9,42.5,47.7,71.2,172.2,173.2.

Ultimate analysis calculated value (%): C, 65.85; H, 9.87; N, 5.49; Measured value (%): C, 66.01; H, 10.08; N, 5.49.

C ₁₄H ₂₅NO ₃(MW=255.26, mass spectrum (MH ⁺256)).

Embodiment B 72

N-[(hexamethylene-1-thiazolinyl) ethanoyl]-L-L-Ala isobutyl ester synthetic

According to above universal method BB, with hexamethylene-1-thiazolinyl acetate (Alfa) and L-L-Ala isobutyl ester hydrochloride (deriving from above Embodiment B B) preparation title compound solid, its fusing point is 49-51 ℃.By silica gel tlc monitoring reaction (Rf=0.40 is at 1: 3 EtOAc: launch in the hexane), and with extracted with diethyl ether then with wet chemical and aqueous hydrochloric acid washing carrying out purifying.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝0.91(d，J＝4.5Hz，3H)，0.93(d，J＝6.7Hz，3H)，1.40(d，J＝7.2Hz，3H)，1.52-1.70(m，4H)，1.97(m，3H)，2.06(bs，2H)，2.89(s，2H)，3.92(m，2H)，4.59(m，1H)，5.65(s，1H)，6.33(d，J＝6.6Hz，1H)。

¹³C-nmr(CDCl ₃)：δ＝18.7，18.91，18.93，21.9，22.7，25.3，27.6，28.3，46.1，47.9，71.4，127.1，132.5，170.6，173.1。

Ultimate analysis calculated value (%): C, 67.38; H, 9.42; N, 5.24; Measured value (%): C, 67.34; H, 9.54; N, 5.16.

C ₁₅H ₂₅NO ₃(MW=267.37, mass spectrum (MH ⁺268)).

Embodiment B 73

The N-[(3-chloro-phenyl-) ethanoyl] L-Ala 3-methyl but-2-ene base thioesters synthetic

According to above universal method BC, use the N-[(3-chloro-phenyl-) ethanoyl] L-Ala and 3-methyl-2-butene thioesters (TCI), the preparation title compound.By silica gel tlc monitoring reaction, and with 3: 7 ethyl acetate: hexane is as eluent, through the liquid chromatography (LC) purifying.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝5.2-5.075(m，1H)，4.37(dq，J＝9Hz，1H)，3.56(s)，3.43(d，J＝12Hz，2H)，1.266(d，J＝12Hz，6H)，1.3(d，J＝9Hz，3H)。

C ₁₆H ₂₀NO ₂ClS (MW=325.86, mass spectrum (MH ⁺325)).

Embodiment B 74

The N-[(2-phenyl)-and 2-fluoro ethanoyl] alanine ethyl ester synthetic

According to above universal method BF, with α-fluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the preparation title compound.By silica gel tlc monitoring reaction (Rf=0.75 is 1: 1 ethyl acetate: launch in the hexane), and with 1: 2 ethyl acetate: hexane is as eluent, through the silica gel column chromatography purifying.

The NMR data are as follows:

¹H-nmr(DMSO-d ₆)：δ＝1.14(q，3H)，1.34(d，3H)，4.07(m，2H)，4.33(m，1H)，5.84(d，1H)，6.01(d，1H)，7.40-7.55(m，5H)，8.87(m，1H)。

C ₁₃H ₁₆NO ₃F (MW=253.27, mass spectrum (MH ⁺253)).

Embodiment B 75

Synthesizing of N-(3,5-difluorophenyl ethanoyl)-L-phenyl glycine methyl ester

According to above universal method BF, with 3,5-difluorophenyl acetic acid (Aldrich) and L-phenyl glycine methyl ester hydrochloride (Bachem) preparation title compound.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.4-7.3(m，5H)，6.9-6.7(m，3H)，6.55(d?1H，7.1Hz)，5.56(d?1H，7Hz)，3.72(s，3H)，3.57(s，2H)。

¹³C-nmr(CDCl ₃)：δ＝197.6，177.6，171.8，169.3，136.7，129.6，129.3，127.8，113.0，112.9，112.7，111.4，103.8，103.5，65.1，57.2，53.5，45.1，43.3，43.3。

C ₁₇H ₁₅NO ₃F ₂(MW=319.31, mass spectrum (MH ⁺330)).

Embodiment B 76

Synthesizing of N-(3,5-difluorophenyl ethanoyl)-L-phenylglycocoll isobutyl ester

By above universal method BF, with 3, the EDC coupling takes place with L-phenyl glycine methyl ester hydrochloride (Bachem) in 5-difluorophenyl acetic acid (Aldrich).The compound that produces is placed a large amount of excessive required alcohol.Add the dry sodium hydride of catalytic amount, carry out tlc after the reaction, until the existence that no longer detects raw material.This reaction is with several milliliters of 1N HCl quencher, after the stirred for several minute, and the adding saturated sodium bicarbonate aqueous solution.Reduce the volume of reaction mixture on rotatory evaporator, until removing excessive alcohol, remaining then resistates is absorbed in the ethyl acetate, adds entry again.Organic phase is washed with saturated sodium-chloride water solution, and through dried over mgso.Remove the solvent in this solution on rotatory evaporator, described then crude product is further purified through chromatography.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.35-7.3(m?5H)，6.8-6.7(m?3H)，6.60(d?1H，7Hz)，5.55(d?1H?7.1Hz)，3.9(m?2H)，3.60(s?2H)，1.85(m?1H?7Hz)，0.8(q?6H?7Hz)。

¹³C-nmr(CDCl ₃)：δ＝171.3，169.3，165.4，138.5，137.0，129.5，129.2，127.6，113.1，113.0，112.8，112.7，103.8，103.5，103.2，75.5，57.2，43.4，43.3，28.2，19.3。

C ₂₀H ₂₁NO ₃F ₂(MW=361.39, mass spectrum (MH+362)).

Embodiment B 77

Synthesizing of N-(cyclopentyl ethanoyl)-L-phenyl glycine methyl ester

According to above universal method BD, with NSC 60134 (Aldrich) and L-phenyl glycine methyl ester hydrochloride (Bachem) preparation title compound solid.

The NMR data are as follows:

Embodiment B 78

Synthesizing of N-(cyclopentyl ethanoyl)-L-alanine methyl ester

According to above universal method BD, with NSC 60134 (Aldrich) and L-alanine methyl ester hydrochloride (Sigma) preparation title compound.

The NMR data are as follows:

C ₁₁H ₁₉NO ₃(MW=213.28, mass spectrum (MH ⁺214)).

Embodiment B 79

Synthesizing of N-(cyclopropyl ethanoyl)-L-phenyl glycine methyl ester

According to above universal method BD, with cyclopropyl acetate (Aldrich) and L-phenyl glycine methyl ester hydrochloride (Bachem) preparation title compound.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.35(m，5H)，6.97(bd，J＝7.2Hz，1H)，5.59(d，J＝7.8Hz，1H)，3.71(s，3H)，2.17(m，2H)，1.05-0.95(m，1H)，0.62(m，2H)，0.02(m，2H)。

Embodiment B 80

Synthesizing of N-(cyclopropyl ethanoyl)-L-alanine methyl ester

According to above universal method BD, with cyclopropyl acetate (Aldrich) and L-alanine methyl ester hydrochloride (Sigma) preparation title compound.

The NMR data are as follows:

Embodiment B 81

The N-[(3-nitrophenyl) ethanoyl]-L-methionine(Met) isobutyl ester synthetic

According to above universal method BH, with nitrophenyl-acetic acid (Aldrich) and L-methionine(Met) (Aldrich) preparation title compound brown oil.By silica gel tlc monitoring reaction.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝8.16(m，2H)，7.67(d，1H)，7.32(t，1H)，6.31(bd，1H)，4.69(m，1H)，3.90(d，2H)，3.68(s，2H)，2.47(t，2H)，2.15(m，1H)，2.02(s，3H)，1.90(m，2H)，0.91(d，6H)。

C ₁₇H ₂₄N ₂O ₅S (MW=368.4, mass spectrum (MH ⁺368)).

Following universal method and embodiment explanation can be used for preparation example synthetic as with the various lactan of following formula VII and VIII compound and related compound.

Universal method III-A

First kind of EDC couling process

In the dichloromethane mixture of 0 ℃, 1: 1 corresponding carboxylic acid and described corresponding amino acid ester or acid amides, add 1.5 equivalent triethylamines, add 2.0 equivalent hydroxybenzotriazole monohydrates then, add 1.25 equivalent ethyl-3-(3-dimethylamino) propyl carbodiimide diimmonium salt hydrochlorate then.Reaction mixture stirred under room temperature spend the night, be transferred in the separating funnel then.Mixture water, saturated sodium bicarbonate aqueous solution, 1N HCl and saturated sodium-chloride water solution washing, and through dried over mgso.The solution that produces removes on rotatory evaporator and desolvates, and obtains described crude product.

Universal method III-B

Second kind of EDC couling process

In ice-water bath, cool off the mixture of respective acids (1eqv), N-1-hydroxybenzotriazole (1.6eqv), corresponding amine (1eqv), N-methylmorpholine (3eqv) and methylene dichloride (or be DMF for insoluble substance), and stir until obtaining clear solution.Then EDC (1.3eqv) is added in the reaction mixture, allow cooling bath temperature in 1-2 hour the reaction mixture stirring be spent the night then to room temperature.Under vacuum, be evaporated to reaction mixture dried.In this resistates, add 20% wet chemical,, allow it leave standstill then, solidify (then spending the night if desired) until the oily product with the mixture shake well.The solid collected by filtration product with 20% wet chemical, water, 10%HCl and water thorough washing, obtains described product then, is generally pure state.Do not observe racemization.

Universal method III-C

The third EDC couling process

Described carboxylic acid is dissolved in the methylene dichloride.Order adds corresponding amino acid ester or acid amides (1eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2eq.).Apply cooling bath to round-bottomed flask, reach 0 ℃ until this solution.At this moment, add 1.2eq.1-(3-dimethyl aminopropyl)-3-ethyl-carbodiimide hydrochloride.This solution stirring is spent the night, be issued to room temperature at nitrogen pressure.By with saturated aqueous sodium carbonate, 0.1M citric acid and salt water washing organic phase, use dried over sodium sulfate then, reaction mixture.Remove then and desolvate, obtain crude product.

Universal method III-D

The 4th kind of EDC coupling method

Under nitrogen atmosphere, in round-bottomed flask, add the THF solution of corresponding carboxylic acid (1.0eq.), hydroxy benzotriazole hydrate (1.1eq.) and corresponding amine (1.0eq.).Will be an amount of in the well-beaten mixture of alkali (as HunigShi alkali) adding of (for unhindered amina is 1.1eq., then be 2.2eq. for the hydrochloride of amine), add EDC (1.1eq.) then.After stirring 4-17 hour under the room temperature, removal of solvent under reduced pressure, resistates is dissolved in ethyl acetate (or similar solvent) and the water, and with saturated sodium bicarbonate aqueous solution, 1N HCl, salt water washing, through anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains described product.

Universal method III-E

The BOP couling process

In the stirred solution of the DMF of refrigerative N-in ice-water bath (3,5-difluoro phenylacetyl) L-Ala (2mmol), add BOP (2.4mmol) and N-methylmorpholine (6mmol).Reaction mixture was stirred 50 minutes, be incorporated in the DMF solution of 0C refrigerative alpha-amino group-gamma-lactam (2mmol) then.Allow cooling bath temperature in 1-2 hour reaction mixture be stirred spend the night then to room temperature.Add 20% wet chemical (60ml), with this mixture shake well.Do not form solid.This mixture is with ethyl acetate (150ml) washing then, is evaporated to driedly under the vacuum, obtains white solid.Add entry (50ml) then, with this mixture shake well.Filter and collect the precipitation that forms, the water thorough washing with the washing of 1ml ether, obtains described product (51mg.0.16mmol, 7.8%) then.

Universal method III-F

The coupling of acyl chlorides and amino acid ester

To (D, L)-add the described acyl chlorides of 4.6mmol in the 5ml pyridine stirred solution of L-Ala isobutyl ester hydrochloride (4.6mmol).Produce precipitation immediately.Mixture was stirred 3.5 hours, it is dissolved in the 100ml ether, with 10%HCl washing 3 times, with salt water washing 1 time, 20% salt of wormwood washing 1 time, salt water washing 1 time.This solution filters and evaporation through dried over mgso, produces described product.Other amino acid ester also can be used for this method.

Universal method III-G

Carboxylic acid and amino acid ester coupling

With the 20ml THF solution stirring of described carboxylic acid (3.3mmol) and 1.1 '-carbonyl dimidazoles (DCI) 2 hours.Add (D, L)-L-Ala isobutyl ester hydrochloride (3.6mmol), add 1.5ml (10.8mmol) triethylamine then.The reaction mixture stirring is spent the night.Reaction mixture is dissolved in the 100ml ether, with 10%HCl washing 3 times, with salt water washing 1 time, 20% salt of wormwood washing 1 time, salt water washing 1 time.This solution filters and evaporation through dried over mgso, produces described product.Other amino acid ester also can be used for this method.

Universal method III-H

The 5th kind of EDC couling process

The THF solution, amine hydrochlorate (1.0eq.), I-hydroxybenzotriazole hydrate (1.1eq.), the N that in round-bottomed flask, add carboxylic acid (1.1eq.), N-diisopropylethylamine (2.1eq.) adds then that 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (1.1eq).Under nitrogen atmosphere, reaction mixture was stirred 10-20 hour under room temperature.Mixture dilutes with ethyl acetate, with 0.1M HCl (1 * 10ml), saturated sodium bicarbonate (1 * 10ml), water (1 * 10ml) and the salt water washing, through dried over mgso.Remove by filter siccative, vacuum concentrated filtrate.Resistates grinds crystallization then through quick purification by silica gel column chromatography from ethyl acetate and hexane.

Universal method III-I

The 6th kind of EDC couling process

In 0 ℃, N ₂Down, in the solution of the THF (0.05-0.1M) of the hydrochloride (1.0eq.) of amine or amine or suspension, add carboxylic acid (1.0-1.1eq.), hydroxybenzotriazole monohydrate (1.1-1.15eq.), HunigShi alkali (for unhindered amina 1.1eq., for amine hydrochlorate 1.1-2.3eq.), add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1.1-1.15eq.) then.Remove cooling bath, mixture is warmed to room temperature 10-24 hour.With for the EtOAc of 3-5 times of volume of initial THF volume dilutes above-mentioned solution or mixture,, use rare NaHCO more respectively with the 0.1-1.0M HCl aqueous solution (1 or 2 *) washing ₃The washing of (1 or 2 *) and salt solution (1 *).Then, with organic phase MgSO ₄Or Na ₂SO ₄Drying is filtered, and concentrates the crude product product is provided, and it is further purified or not purified use.

Universal method III-J

The EEDQ couling process

Under room temperature, nitrogen, to the THF of described amine solution (1.0eq., 0.05-0.08M; whole volumetric molar concentration) amino acid (1.1eq. perhaps is a solid, perhaps the THF solution that adds by intubate) that adds the N-t-Boc protection in; add then EEDQ (Aldrich, 1.1eq.).Under room temperature, pale yellow solution was stirred 16-16.5 hour, then with ethyl acetate dilution (being 3-5 times of volume of original THF volume), with 1M aqueous hydrochloric acid (2 *), dilute aqueous solution of sodium bicarbonate (2 *) and salt solution (1 *) washing.Organic phase is filtered and is concentrated through sodium sulfate or dried over mgso.

Embodiment 2-A

5-amino-5, the synthesis step A-5-oximido-5 of 7-dihydro-6H-dibenzo [a, c] ring heptan-6-alcohol hydrochloride, 7-dihydro-6H-dibenzo [a, c] suberene-6-ketone synthetic

In round-bottomed flask, add 5,7-dihydro-6H-dibenzo [a, c] suberene-6-ketone (1.0g, 4.81mmol) (CAS# 1139-82-8 presses Tetrahedron Letters, the 28th volume, the 23rd phase, (1987), prepare described in the 2633-2636 page or leaf) and butyl nitrite (0.673ml, 5.77mmol) ether solution of (Aldrich).Solution is cooled to 0 ℃, drips saturated HCl (g)/diethyl ether solution and handle.In 0 ℃ after 5 hours, filter the precipitation that produces, with the cold diethyl ether flushing, vacuum-drying produces the title compound colorless solid.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.26-7.74(m，8H)，3.84(m，2H)。

C ₁₅H ₁₁NO ₂(MW=237.26); Mass spectrum (MH ⁺) 238.

C ₁₅H ₁₁NO ₂The analytical calculation value: C, 75.93, H, 4.67 N, 5.90.Measured value: C, 75.67 H, 4.83 N, 5.67.Step B-5-amino-5, the closing of 7-dihydro-6H-dibenzo [a, c] suberene-6-alcohol hydrochloride

Become

(0.489g 2.04mmol) is dissolved among the THF, drops in the mixture of well-beaten LAH (10.2ml.10.2mmol)/THF with above isolated compound.Under nitrogen atmosphere, be heated to backflow after 25 hours, according to the quencher of Fieser method and this solution of processing.The solid that produces with ammoniacal liquor saturated/the chloroform flushing, evaporated filtrate, title compound is through chromatography purification (silicon-dioxide, chloroform).

C ₁₅H ₁₅NO (MW=225.290); Mass spectrum (MH ⁺) 226.

C ₁₅H ₁₅The analytical calculation value of NO: C, 79.97 H, 6.71 N, 6.22.Measured value: C, 80.19 H, 6.71 N, 5.91.

Universal method 5-A

The N-alkylation of lactan

To the alpha-amino group hexanolactam of BOC protection (6.87g, in the solution that DMF 30mmol) (150ml) stirs gradation add 97%NaH (1.08g, 45mmol).Produce bubble immediately, produce a large amount of precipitations then.After 10 minutes, and the adding bromotoluene (3.93ml, 33mmol).Precipitation is dissolving rapidly, obtains clear solution in about 10 minutes.The reaction mixture stirring is spent the night, on rotatory evaporator, as far as possible fully evaporate then in 30 ℃.Ethyl acetate (100ml) is added in the resistates, and this mixture water, salt water washing are through dried over mgso.After filtering and concentrating, obtain thick liquid (10g), then it is separated through silica gel column chromatography, as eluent, obtain 5.51g (58%) N-benzyl product oily matter with 1: 3 ethyl acetate/hexane.Other lactan and alkylating agent can be used for this method, obtain all N-alkylation lactan.Such as LiN (SiMe ₃) various alkali also can use.

Universal method 5-B

BOC removal method

Stir 1: 1-2: the compound of the BOC protection in 1 methylene dichloride and the trifluoroacetic acid mixture, show conversion fully until tlc, be generally 2 hours.Then this solution is stripped to driedly, resistates is absorbed in ethyl acetate or the methylene dichloride.This solution washs with saturated sodium bicarbonate aqueous solution, and water is transferred to alkaline pH, then with ethyl acetate or dichloromethane extraction.Organic phase is washed with saturated sodium-chloride water solution, and through dried over mgso.On rotatory evaporator, remove the solvent in this solution, obtain described product.

Universal method 5-C

Synthesizing of alpha-amino group lactan

Use Olah, Org.Synth.Collective, VII volume, the sulfonic acid azanol described in the 254th page carry out the Schmidt reaction of 4-ethyl cyclohexanone, obtain 5-ethyl hexanolactam, and yield is 76%.Then, adopt Watthey etc., J.Med.Chem., 1985,28, method described in the 1511-1516 is used PCl ₅This lactan in α position dichloride, by hydro-reduction, is obtained four kinds of isomery monochlorides (two kinds of racemic mixtures) then.Two kinds of racemic mixtures are separated from one another through silica gel column chromatography, make every kind of racemic mixture and reaction of sodium azide, produce corresponding trinitride, with its hydrogenation, obtain corresponding alpha-amino group lactan.Other naphthenone can be used for this method, and all alpha-amino group lactan are provided.In some cases, such as when 9 yuan of rings of preparation alpha-amino group lactan, can need the long reaction times, higher temperature of reaction and excessive sodiumazide.For example 9 yuan of ring alpha-amino group lactan needs 5 equivalent sodiumazide, temperature of reaction are 120 ℃, and the reaction times is 4 days.This class condition can easily be determined by those skilled in the art.

Universal method 5-D

4-amino-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Can be by following methods known in the art, preparation is used for the present invention's 4-amino-1,2,3,4-tetrahydroisoquinoline-3-ketone.The condition of these reactions is at D.Ben-Ishai etc., Tetrahedron, and 43,439-450 further describes in (1987).Following intermediate prepares by this method:

3-amino-1,2,3,4-tetrahydroisoquinoline-3-ketone

4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-ketone

4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone

Cis and trans 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone

4-amino-2-styroyl-1,2,3,4-tetrahydroisoquinoline-3-ketone

4-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-ketone

9-amino (fluorenes-1-yl) glycine δ-lactan-1,2,3,4-tetrahydroisoquinoline-3-ketone.

The preparation of the two methoxycarbonyl Padils of steps A-N-: add the Urethylane of two molar equivalents and the naphthene sulfonic acid of 0.1 molar equivalent in the Glyoxylic acid hydrate of the molar equivalent (mole equivalent) in 2 liters of no alcoholic acid chloroforms.Then with this reaction mixture refluxed 6 hours.Remove moisture content with reverse dean stark trap.Cool off reactant then, filtration product is washed with chloroform.Make white solid recrystallization from ethyl acetate/hexane, obtain white powder, yield is 65%.

Step B: couling process: the EDCHCl, benzylamine, HOBT and the diisopropylethylamine that add a molar equivalent in the two methoxycarbonyl Padils (or suitable carboxylic acid) of the N-of the 0.0291mol in 200ml THF.Under room temperature, this reactant was stirred 18 hours, incline then to separating funnel, use ethyl acetate extraction.Wash ethyl acetate solution successively with 1M salt of wormwood and 1M hydrochloric acid.Through the dried over sodium sulfate organic layer, filter and the removal solvent, obtain the benzamide crystallization of the two methoxycarbonyl Padils of N-.With the not purified use of this material.General yield is 40-55%.

Step C: cyclization method: the benzamide (0.008mol) of the two methoxycarbonyl Padils of N-is dissolved in the 75ml methylsulfonic acid, under room temperature, stirs and spend the night.This reaction mixture is inclined to ice, use ethyl acetate extraction.Wash acetic acid ethyl ester extract successively with 1M salt of wormwood and 1N hydrochloric acid.Through the dried over sodium sulfate organic layer, filter and the removal solvent, obtain crystalline 4-methoxycarbonyl amino-1,2,3,4-tetrahydroisoquinoline-3-ketone, yield is 50-90%.With the not purified use of this material.

Step D: remove methoxycarbonyl (MOC):, add the trimethyl silyl iodine (TMSI) of 2 molar equivalents in 4-tetrahydroisoquinoline-3-ketone (3.4mmol) to the 4-methoxycarbonyl amino-1,2,3 in the 30ml acetonitrile.With this reaction mixture be heated to 50-80 ℃ 3 hours, cool off then and incline to separating funnel.Dilute this reaction mixture with ethyl acetate, wash successively with 1M salt of wormwood and 5% sodium bisulfite.Through the dried over sodium sulfate organic layer, filter.Solvent is removed in decompression, obtains 4-amino-1,2,3,4-tetrahydroisoquinoline-3-ketone derivatives.General yield is 50-87%.

Step e: the other method of removing methoxycarbonyl: in the compound of 3.8mmol MOC-protection, add the acetic acid solution of 10ml 30%HBr, with this reaction mixture be heated to 60 ℃ 3 hours.Cool off this mixture then, add hexane.The hexane layer that inclines places residue under the decompression to obtain brown solid.This solid is made slurry and filtration in ether, obtain 4-amino-1,2,3,4-tetrahydroisoquinoline-3-ketone hydrobromate.General yield is 57-88%.

Embodiment 5-A

3-amino-1,2,3,4-tetrahydroquinoline-2-ketone synthetic

Steps A: (0.30g 110M%) adds in the dehydrated alcohol (45ml), and this reaction mixture is stirred to homogeneous with sodium.(2.51g 100M%), stirs this mixture 1 hour disposable adding N-acetamino diethyl malonate.(2.5g 100M%), stirs this reaction mixture 3 hours disposable then adding 2-nitrobenzyl bromine.This reactant is inclined to water, with ethyl acetate (3 *) extraction, water (3 *) and salt solution (1 *) back scrubbing then.With sal epsom processing, rotary evaporation and chromatography (30% ethyl acetate/hexane), obtain N-acetylaminohydroxyphenylarsonic acid 2-nitrobenzyl diethyl malonate, yield is 82%.

Step B: (1g 100M%) is dissolved in the minimum ethanol with N-acetylaminohydroxyphenylarsonic acid 2-nitrobenzyl diethyl malonate.Adding Pd/C (10%, 0.05g), this reaction mixture was placed the 50psi hydrogen pressure following 3 hours.Filter this reactant by Celite pad then.(catalytic amount 0.01g), refluxes this mixture 2 hours to add ethanol (25ml) and TsOH again.This reactant of rotary evaporation obtains residue, and it is allocated between water and the ethyl acetate.With ethyl acetate (3 *) aqueous layer extracted, water (3 *) and salt solution (1 *) wash the acetic acid ethyl ester extract that merges successively.Handle and rotary evaporation with sal epsom, obtain pure product 3-(N-kharophen)-3-carbonyl oxyethyl group-1,2,3,4-tetrahydroquinoline-2-ketone (yield 89%).

Step C: with 3-(N-kharophen)-3-carbonyl oxyethyl group-1,2,3, (0.75g 100M%) was suspended in the 6N hydrochloric acid (25ml) 4-tetrahydroquinoline-2-ketone, with this mixture heating up to 100 ℃ 3 hours.Cool off this reactant, rotary evaporation is a residue, and it is allocated between water and the ethyl acetate.With ethyl acetate (3 *) aqueous layer extracted, water (3 *) and salt solution (1 *) wash the acetic acid ethyl ester extract that merges successively then.Handle through sal epsom, subsequently rotary evaporation obtain 3-(R, S)-amino-1,2,3,4-tetrahydroquinoline-2-ketone (yield 72%).

Embodiment 5-B

4-amino-1-(pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: (Aldrich drips 1.1eq. phenyl-magnesium-bromide (Aldrich) in 300ml anhydrous ether solution 0.150mol) to the 4-cyanopyridine.This reactant was refluxed 2 hours, under room temperature, stir then and spend the night.Drip and be the sodium borohydride (1.0eq.) of 200ml methanol solution (note: heat release is violent).Then this reactant is heated to and refluxed 6 hours, cooling and with saturated ammonium chloride solution quencher.Inclining from the salt of reaction mixture solution, uses the 1N hcl acidifying.Behind ethyl acetate washing water layer, the pH of water layer is transferred to about 9.0 with 1N sodium hydroxide (cold).Use the ethyl acetate extraction water layer then,,, filter and concentrate, obtain 4-pyridyl-α-benzylamine, be dense yellow oil through dried over sodium sulfate with salt water washing organic extract.

Step B:,, prepare this title compound with 4-pyridyl-α-benzylamine according to the method for universal method 5-D.

Embodiment 5-C

4-amino-1-(pyridine-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: according to method described in the embodiment 5-B, replace the 4-cyanopyridine, preparation 2-pyridyl-α-benzylamine with 2-cyanopyridine (Aldrich).

Embodiment 5-D

4-amino-1-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: according to J.Med.Chem., 1982,25, method described in 1248, with 3-benzoyl-pyridine (Aldrich), preparation 3-pyridyl-α-benzylamine.

Step B:,, prepare this title compound with 3-pyridyl-α-benzylamine according to the method for universal method 5-D.

Embodiment 5-E

4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: (0.044mol adds 10g 5%Pd/C in 150ml ethyl acetate Aldrich) and the Parr bottle of 4.5ml concentrated sulfuric acid solution to containing 3-benzoyl phenylformic acid.Under hydrogen (45psi), the hydrogenation on the Parr device of this mixture is spent the night.Filter this reaction mixture by Hyflo then, wash with ethyl acetate.Through dried over sodium sulfate filtrate, filter and the concentrated oily matter that obtains.With hexane this oily matter is made slurry, the white solid that filter to collect produces obtains the 3-benzylbenzoic acid, with it without being further purified use.

Step B: in the product (0.0119mol) of steps A, add 150ml methylene dichloride, 1 DMF, 10ml oxalyl chloride, under room temperature, this mixture was stirred 3 hours.After being cooled to 10 ℃, add 30ml ammonium hydroxide (heat release), this mixture was stirred 30 minutes.Concentrate this reaction mixture then, with the residue of ethyl acetate dilution generation.With 1N sodium hydroxide and salt water washing organic layer, through dried over sodium sulfate and concentrate, obtain 3-(benzyl) benzamide into white solid, with it without being further purified use.

Step C: in 70 toluene solutions of the 3-that derives from step B (benzyl) benzamide (.0094mol), add 8ml Red-Al  (toluene solution of two (2-methoxy ethoxy) sodium aluminum hydrides of 65+wt.%, Aldrich) (note: exothermic heat of reaction is violent).Then this reaction mixture was heated 2 hours at 60 ℃, in extremely icing with hypsokinesis.With the mixture that ethyl acetate extraction produces, the extract that water and salt water washing merge.With 1N hcl as extraction agent organic layer, wash water layer with ethyl acetate.With 1N sodium hydroxide the pH of water layer is transferred to approximately 9.0 then, use ethyl acetate extraction.Water and salt water washing organic extract concentrate then and obtain 3-(benzyl) benzylamine.

Step D:,, prepare this title compound with 3-(benzyl) benzylamine according to universal method 5-D.

Embodiment 5-F

4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: (Aldrich drips 1.5eq LAH (among the THF of 1M) solution in 150ml THF solution 0.025mol) to the 4-biphenyl carboxamides that is cooled to 10 ℃.This reaction mixture is become green uniform solution, is become yellow uniform solution subsequently by white slurry.Use this reactant of 2.5ml 1N sodium hydroxide quencher then.Then filter this mixture, use ethyl acetate extraction by Hyflo.Use 1N salt acid elution organic layer then.With 1N sodium hydroxide the pH of the water layer that produces is transferred to approximately 9, use ethyl acetate extraction.Water and salt water washing organic extract then through dried over sodium sulfate, filter and concentrate, and obtain 4-(phenyl) benzylamine, are white solid.

Step B:,, prepare this title compound with 4-(phenyl) benzylamine according to universal method 5-D.

Embodiment 5-G

Cis and trans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: according to universal method 5-D, with α-phenylbenzylamine (Aldrich), preparation 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone.

Step B:, add 2.0eq triethylamine and Boc acid anhydrides (1.1eq.) in the 20ml dichloromethane solution of 4-tetrahydroisoquinoline-3-ketone (0.00158mol) to the 4-amino-1-phenyl-1,2,3 that derives from steps A.Under room temperature, this reactant stirring is spent the night, concentrate then.With ethyl acetate and water dilution residue.With sodium pyrosulfate the pH of water layer is transferred to 3.0, separate each layer.Organic layer filters and concentrates through dried over sodium sulfate.Residue with ethyl acetate/hexane (70: 30) wash-out, obtains containing cis and trans-4-(N-Boc-amino)-1-phenyl-1,2,3, the white solid of 4-tetrahydroisoquinoline-mixture of 1: 1 of 3-ketone isomer through LC 2000 chromatography purifications.Make this mixture recrystallization from ethyl acetate, the cis and the trans-isomer(ide) mixture that obtain pure product trans-isomer(ide) and be rich in cis-isomeride.Make this mixture once more from ethyl acetate/hexane (70: 30) recrystallization obtain pure product cis-isomeride.

Step C: according to universal method 8-J, cis-isomeride and the trans-isomer(ide) that derives from step B gone protection respectively, obtain cis-4-amino-1-phenyl-1; 2,3,4-tetrahydroisoquinoline-3-ketone and trans-4-amino-1-phenyl-1; 2,3,4-tetrahydroisoquinoline-3-ketone.

Embodiment 5-H

4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: (Aldrich drips tert-butyl lithium (2eq., 1.7M hexane solution) in 300ml anhydrous THF solution 0.0858mol) to the 1-bromo-3-phenyl benzene that is cooled to-78 ℃.In-78 ℃, this reaction mixture was stirred 40 minutes, use DMF (13.24ml) quencher of 2eq. then.The mixture that produces was stirred 20 minutes, incline then to separating funnel, use dichloromethane extraction.Wash organic extract with water,, filter and concentrate, obtain brown oil through dried over sodium sulfate.This oily matter through LC 2000 chromatography purifications, is obtained 3-xenyl formaldehyde with ethyl acetate/hexane (5: 95) wash-out.

Step B: the 7N ammonia/methanol solution and the sodium cyanoborohydride (2eq.) that in the 30ml methanol solution of 3-xenyl formaldehyde (0.011eq.), add 10eq..Yellow jelly is precipitated out from solution.Then this solution is heated to jelly in 60 ℃ and dissolves, under room temperature, this solution stirring is spent the night.Concentrate this reaction mixture then, with the residue of frozen water and ethyl acetate dilution generation.Use salt water washing organic layer then, use the 5N hcl as extraction agent.The pH of water layer is transferred to 12, use the cold ethyl acetate aqueous layer extracted.Through the dried over sodium sulfate organic layer, filter and concentrate, obtain 3-(phenyl) benzylamine, be oily matter.

Step C:, prepare this title compound with 3-(phenyl) benzylamine according to universal method 5-D.

Embodiment 5-I

4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinoline-3-ketone synthetic

Steps A: (0.123mol drips 2.0eq. phenylethylamine (Aldrich) in 600ml dichloromethane solution Aldrich) to Benzoyl chloride.Under room temperature, this reaction mixture was stirred 3 hours, incline then to separating funnel, use dichloromethane extraction.Water and 1N salt acid elution organic extract through dried over sodium sulfate, filter and concentrate, and obtain N-styroyl benzamide.

Step B: adopt the method for embodiment 5-E step C, reduction N-styroyl benzamide obtains the N-benzyl-N-phenyl-ethyl amine into oily matter.

Step C:,, prepare this title compound with N-benzyl-N-phenyl-ethyl amine according to universal method 5-D.

Embodiment 5-J

Synthesizing of 3-amino-1-methyl-2-dihydroindolone one hydrochloride

Steps A: according to Ben-Ishai, D.; Sataty, I.; Peled, N.; Goldshare, R. are at Tetrahedron 1987,43, and method described in the 439-450 prepares (2,3-dihydro-1-methyl-2-oxo-1H-indol-3-yl) Urethylane (CAS No.110599-56-9).This preparation method's raw material be methylphenylamine (CAS# 100-61-8, Eastman Kodak, Co.), Glyoxylic acid hydrate (CAS# 298-12-4, Aldrich) and Urethylane (CAS# 598-55-0, Aldrich).

Step B: AcOH (10ml) solution of 31%HBr that will derive from the product (333.5mg) of steps A be heated to 50-60 ℃ 2 hours.Concentrate the orange solution that produces and obtain dense orange, it is dissolved in the ethyl acetate (15ml), with 1M aqueous hydrochloric acid (10ml) extraction product.With the sodium bicarbonate aqueous solution neutralizing acid aqueous solution, with methylene dichloride (10 * 10ml) extraction products.In the dichloromethane extract that merges, feed hydrogen chloride gas and form purple solution.Concentrate this solution and obtain being purple solid title compound (262.8mg).

Embodiment 5-K

3-amino-1-methyl-4-phenyl-3,4-is trans-dihydro-quinolone/tin title complex synthetic

Steps A: 4-phenyl-3,4-dihydro-quinolone synthetic

According to Conley, R.T.; Knopka, W.N. be at J.Org.Chem.1964, and 29, method described in the 496-497 prepares 4-phenyl-3 with two-stage process, 4-dihydro-quinolone (CAS#4888-33-9).This preparation method's raw material is cinnamyl chloride (Aldrich) and aniline (Aldrich).Through this title compound of flash chromatography purifying, with dichloromethane/ethyl acetate (4: 1) wash-out.

Step B:1-methyl-4-phenyl-3,4-dihydro-quinolone synthetic

Under 0 ℃, nitrogen, with 5 minutes, in THF (50ml) suspension of sodium hydride (1.2eq., 0.537g60% mineral oil dispersion liquid), add product (1.0eq., THF 2.50g) (50ml) solution that derives from steps A by conduit.In 0 ℃, the pale yellow mixture that produces was stirred 10 minutes, add then methyl-iodide (2.0eq., 1.39ml).Under agitation with opaque yellow mixture slowly (not removing ice bath) temperature to room temperature 15 hours.Add 1M aqueous hydrochloric acid (50ml) and ethyl acetate (250ml), each alternate distribution.With rare sodium bicarbonate (1 * 100ml) and salt solution (1 * 100ml) washing organic phase then through dried over mgso, is filtered, concentrate, residue through the flash chromatography purifying, is used dichloromethane/ethyl acetate (19: 1 to 15: 1 gradient elutions), obtain 1-methyl-4-phenyl-3, the 4-dihydro-quinolone.

Step C:3-azido--1-methyl-4-phenyl-3,4-is trans-dihydro-quinolone synthetic

According to universal method 8-K, be prepared as the 3-azido--1-methyl-4-phenyl-3 of white solid, 4-is trans-dihydro-quinolone.This product through the flash chromatography purifying, is used 15: 15: 1 wash-outs of dichloromethane/hexane/ethyl acetate.

The selection of this title compound ¹H-NMR (CDCl ₃) data: δ=4.46 (d, 1H, J=10.57Hz), 4.18 (d, 1H, J=10.63Hz).

Step D:3-amino-1-methyl-4-phenyl-3,4-is trans-dihydro-quinolone/tin title complex synthetic

Under 0 ℃, nitrogen, by conduit with 1 minute the clockwise tindichloride (350.7mg) methyl alcohol (7rml) mixed solution in add MeOH/THF (5ml/5ml) solution that derives from step C product (257.4mg).Remove cooling bath, with this solution temperature to room temperature 8 hours (through the no raw material existence of TLC monitoring).Concentrate this solution and obtain yellow foam.Add THF (10ml), this mixture is concentrated once more, and without being further purified use.

Embodiment 5-L

3-amino-1-methyl-4-phenyl-3,4-cis-dihydro-quinolone synthetic

Steps A: 3-amino-1-methyl-4-phenyl-3, the trans dihydro-quinolone of 4-synthetic

According to universal method 8-F, with the 3-azido--1-methyl-4-phenyl-3 that derives from embodiment 5-K step C, the trans dihydro-quinolone of 4-, preparation 3-amino-1-methyl-4-phenyl-3, the trans dihydro-quinolone of 4-.This product with ethyl acetate/hexane (4: 1) wash-out, obtains white solid through the L.C.2000 purifying.

This title compound is selected ¹H-NMR (CDCl ₃) data: δ=4.03 (d, 1H, J=12.8Hz), 3.92 (d, 1H, J=12.7Hz).

Step B:3-(4-benzyl chloride base imines)-1-methyl-4-phenyl-3,4-is trans-dihydro-quinolone synthetic

Under room temperature, nitrogen, to the product that derives from steps A (1eq., add in methylene dichloride 239.6mg) (10ml) solution 4-chlorobenzaldehyde (1.05eq., 140mg, Aldrich), triethylamine (1.4eq., 185ml) and sal epsom (3.6eq., 411mg).Under room temperature, the mixed solution that produces was stirred 73 hours.Filter to remove solid by Celite pad, use dichloromethane rinse, concentrated filtrate obtains 3-(4-benzyl chloride base imines)-1-methyl-4-phenyl-3, and 4-is trans-dihydro-quinolone, be the thickness white foam.

Step C:3-amino-1-methyl-4-phenyl-3,4-cis-dihydro-quinolone synthetic

In-78, under the nitrogen, (1.05eq. added n-Butyl Lithium (1.05eq., the hexane solution of 0.588ml 1.6M) in THF 0.132ml) (5ml) solution, with the solution stirring that produces 30 minutes to Diisopropylamine.In this solution, add product (1.0eq., THF 336mg) (2ml) solution that derives from step B by conduit.With this solution temperature to 0 ℃, use 1M aqueous hydrochloric acid (3ml) quencher then, under agitation temperature is to ambient temperature overnight.The water extraction product with ethyl acetate (1 *) washing, through 1M wet chemical alkalization aqueous acid, is used the ethyl acetate extraction product then.Use the dried over sodium sulfate acetic acid ethyl ester extract, filter and concentrate, obtain 3-amino-1-methyl-4-phenyl-3,4-cis-dihydro-quinolone.

The selection of this title compound ¹H-NMR (CDCl ₃) data: δ=4.31 (d, 1H, J=6.6Hz).

Embodiment 5-M

3-amino-1-tert-butyl ester base-4-phenyl-3,4-is trans-

Synthesizing of dihydro-quinolone/tin title complex

Steps A: 1-tert-butyl ester base-4-phenyl-3,4-dihydro-quinolone synthetic

According to Grehn, L.; Gunnarsson, K.; Ragnarsson, U.Acta ChemicaScandinavica B 1986,40, the Boc method of the described arylamide of 745-750, with (Boc) 2O (Aldrich) and catalytic DMAP (Aldrich) in acetonitrile, by product (CAS# 4888-33-9) the preparation 1-tert-butyl ester base-4-phenyl-3 of embodiment 5-K steps A, 4-dihydro-quinolone.Through this product of flash chromatography purifying, use CH ₂Cl ₂To CH ₂Cl ₂The gradient elution of/EtOAc (19: 1) separates as faint yellow oily thing.

Step B:3-azido--1-tert-butyl ester base-4-phenyl-3,4-is trans-dihydro-quinolone synthetic

According to universal method 8-K, with the product that derives from steps A, be prepared as the title compound of 12.4: 1 trans/cis mixture of isomers, separate through flash chromatography, in first post,, in second post, use hexane/ethyl acetate (12: 1) wash-out with hexane/ether (6: 1 to 4: 1 gradient elutions).Pure product trans-isomer(ide) is used for step C.

The selection of this title compound ¹H-NMR (CDCl ₃) data: δ=4.45 (d, 1H, J=11.1Hz), 4.24 (d, 1H, J=11.2Hz).

Step C:3-amino-1-tert-butyl ester base-4-phenyl-3,4-is trans-dihydro-quinolone/tin title complex synthetic

Under 0 ℃, nitrogen, by conduit with 1 minute the clockwise tindichloride (450.6mg) methyl alcohol (9ml) mixed solution in add methyl alcohol (15ml) solution of the product (433.0mg) that derives from part D.Remove cooling bath, with this solution temperature to room temperature 17 hours.Concentrate this solution and obtain the amorphous yellow solid, with it without being further purified use.

Embodiment 5-N

(S)-3-amino-1-benzyl-δ-Valerolactim synthetic

Synthesizing of steps A: L-(+)-ornithine methyl ester hydrochloride

It is saturated to solution to feed dry hydrogen chloride gas in the methanol suspension of L-(+)-ornithine hydrochloride (Aldrich) that stirs.With this reaction mixture of Rubber Diaphragm Seal, under room temperature, continue to stir to spend the night.Solvent is removed in decompression then, grinds residue with ether.The solid that drying under reduced pressure produces obtains L-(+)-ornithine methyl ester hydrochloride (yield 97%) into white solid.

Step B:(S)-the amino δ-Valerolactim of 3-synthetic

(2.0eq. Aldrich), slowly adds methyl alcohol (2.3ml/mmol) with the spherical sodium in hexane (2 *) washing oil.Under nitrogen, stir this reaction mixture to sodium and dissolve, drip methyl alcohol (2.3ml/mmol) solution of L-(+)-ornithine methyl ester hydrochloride (1eq.) then.This reaction mixture was stirred 16 hours, use ether (5ml/mmol) dilution then, filter and remove solid.Solvent is removed in decompression subsequently, down residue is heated 3 hours at 70 ℃ in decompression.Grind residue with methylene dichloride/ether, inclining solvent, and the residue that drying under reduced pressure produces obtains (S)-3-amino-δ-Valerolactim (yield 44%).

Synthesizing of step C:N-Boc-(S)-3-amino-δ-Valerolactim

(S)-3-amino-δ-Valerolactim (1eq.) is dissolved in the diox, this solution is cooled to 0 ℃.Add BOC-acid anhydrides (1.3eq.), remove ice bath, make the solution temperature, continue to stir 16 hours to room temperature.Rotary evaporation solution obtains N-Boc-(S)-3-amino-δ-Valerolactim.

Step D:(S)-3-amino-1-benzyl δ-Valerolactim synthetic

According to universal method 5-A,, obtain N-Boc-(S)-3-amino-1-benzyl-δ-Valerolactim with N-Boc-(S)-3-amino-δ-Valerolactim and bromotoluene.Remove the Boc group according to universal method 5-B and obtain title compound.

Embodiment 5-O

Synthesizing of 4-amino-2-azepine-2-benzyl-3-oxo dicyclo [3.2.1] octane hydrochloride

Steps A: 2-azepine-3-oxo dicyclo [3.2.1] octane and 3-azepine-2-oxo dicyclo [3.2.1] octane (9: 1 mixtures) synthetic

Azanol (the hydroylamine)-O-sulfonic acid that in the 1ml/mmol acetate of (±)-Norcamphor (Aldrich), adds 1.5eq..Under nitrogen, this reaction mixture is heated to backflow 1 hour, add saturated yellow soda ash and dilute sodium hydroxide then.With the mixture that dichloromethane extraction produces, with salt water washing organic extract, through dried over sodium sulfate, solvent is removed in decompression.Through the column chromatography purification residue, obtain 9: 1 2-azepine-3-oxo dicyclo [3.2.1] octane and the mixture of 3-azepine-2-oxo dicyclo [3.2.1] octane.

Synthesizing of step B:2-azepine-2-benzyl-3-oxo dicyclo [3.2.1] octane

According to universal method 5-A, with the product and the bromotoluene of steps A, preparation 2-azepine-2-benzyl-3-oxo dicyclo [3.2.1] octane.

Synthesizing of step C:2-azepine-2-benzyl-4-oximido-3-oxo dicyclo [3.2.1] octane

The 1M t-BuOK/THF (Aldrich) that adds 2.5eq. in the THF solution of 2-azepine-2-benzyl-3-oxo dicyclo [3.2.1] octane stirs the mixed solution that produces 30 minutes.Drip Isopentyl nitrite (1.5eq.) then, this reaction mixture is stirred spend the night.In this reaction mixture, add 3N hydrochloric acid,, wash organic extract with water, dry and concentrating under reduced pressure with this mixture of ethyl acetate extraction.Grind residue with ether/hexane, incline and desolvate, the drying under reduced pressure residue obtains 2-azepine-2-benzyl-4-oximido-3-oxo dicyclo [3.2.1] octane (yield 41%) into brown liquid.This method also by Y.Kim in Tetrahedron Lett.30 (21), describe among the 2833-2636 (1989).

Synthesizing of step D:2-azepine-2-benzyl-4-amino-3-oxo dicyclo [3.2.1] octane

2-azepine-2-benzyl-4-oximido-10ml/mmol the ethanol of 3-oxo dicyclo [3.2.1] octane and the solution of 5.8ml/mmol 3N hydrochloric acid that will contain 0.5g/mmol 10%Pd/C are saturated to 45psi with hydrogen.With this mixture jolting 3 hours, filter by diatomite layer then.Through dried over sodium sulfate filtrate, concentrating under reduced pressure obtains being solid title compound (yield 86%).This method also by E.Reimann at Arch.Pharm.310, describe among the 102-109 (1977).

Universal method 6-A

1-amino-1,3,4, the alkylation of 5-tetrahydrochysene-2H-3-benzo-aza -2-ketone

Steps A: according to Ben-Ishai etc. at Tetrahedron, the method described in 1987,43,430, preparation 1-ethoxycarbonyl amino-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza -2-ketone.

Step B: with 1-ethoxycarbonyl amino-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza -2-ketone (2.0g 100M%) is dissolved among the DMF (30ml), and disposable adding NaH (95%, 0.17g, 100M%).This reaction mixture was stirred 1 hour, add suitable alkyl iodide (300M%) then, this mixture was stirred 12 hours.This reactant is inclined to water, with ethyl acetate (3 *) extraction.Water (3 *) and salt solution (1 *) wash acetic acid ethyl ester extract then.With sal epsom processing, rotary evaporation and chromatography (30% ethyl acetate/hexane wash-out), obtain 1-ethoxycarbonyl amido-3-alkyl-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza -2-ketone, yield 87%.

Step C: with 1-ethoxycarbonyl amido-3-alkyl-1,3,4, (1.0g 100M%) is suspended among the 30ml 30%HBr/HOAc 5-tetrahydrochysene-2H-3-benzo-aza -2-ketone, and is heated to 100 ℃.Under this temperature above-mentioned reaction mixture was stirred 5 hours, cool off this reactant and rotary evaporation then, obtain 1-amido-3-alkyl-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza -2-ketone is hydrobromate (100% yield).

Universal method 6-B

3-amino-1,3,4, the alkylation of 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone

Steps A: at Tetrahedron Letters, the method described in 1994,35,3239 prepares 3-amino-1,3,4 by α-Tetralone an intermediate of Sertraline, 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone according to Armstrong etc.To be used for the following step according to the following compounds of this method preparation:

5-methyl-3-amino-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (by 4-methyl-α-Tetralone an intermediate of Sertraline (Aldrich) preparation); With

5,5-dimethyl-3-amino-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (by 4,4-dimethyl (dimethyul)-α-Tetralone an intermediate of Sertraline (Aldrich) preparation).

Step B: with 3-amino-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (4.43g 100M%) is suspended in the trimethyl carbinol (30ml), and dropping BOC-acid anhydrides (7.5ml, 130M%).This reactant was stirred 2 hours, and rotary evaporation is a residue then, and it through chromatography, with 60% ethyl acetate/hexane wash-out, is obtained the 3-amino-1,3,4 of BOC-protection, 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone, and yield is 87%.

Step C: with the 3-amino-1,3,4 of BOC-protection, 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (1.5g 100M%) is dissolved among the DMF (20ml), and disposable adding NaH (95%, 0.13g, 100M%).This reaction mixture was stirred 1 hour, add suitable alkyl iodide (300M%) then, continue to stir 12 hours.This reactant is inclined to water, with ethyl acetate (3 *) extraction.Water (3 *) and salt solution (1 *) wash acetic acid ethyl ester extract then.With sal epsom processing, rotary evaporation and chromatography (30% ethyl acetate/hexane wash-out), obtain the 3-amino-1-alkyl-1,3,4 of BOC-protection, 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone, yield 80%.

Step D: with the 3-amino-1-alkyl-1 of BOC-protection; 3; 4, (1.0g 100M%) is suspended in methylene dichloride/trifluoroacetic acid of 1: 1 of 30ml 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone; said mixture was stirred 4 hours; rotary evaporation obtains 3-amino-1-alkyl-1,3 then; 4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (100% yield).

Embodiment 6-A

3-amino-1,5-dimethyl-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone synthetic

Steps A: at Tetrahedron Letters, the method described in 1994,35,3239 prepares 3-amino-5-methyl isophthalic acid by 4-methyl-α-Tetralone an intermediate of Sertraline according to Armstrong etc., and 3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone.

Step B: with 3-amino-5-methyl isophthalic acid, 3,4, (9.3g 100M%) is dissolved in the diox (300ml) 5-tetrahydrochysene-2H-1-benzo-aza -2-ketone, and this solution is cooled to 0 ℃.(13.89g 130M%), removes ice bath, makes this solution temperature to room temperature, continues to stir 16 hours to add the BOC-acid anhydrides.This solution removal diox of rotary evaporation obtains pale solid.Make this solid recrystallization from chloroform, obtain the 3-amino-5-methyl isophthalic acid of BOC-protection, 3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone, yield is 55%.

Step C: with the 3-amino-5-methyl isophthalic acid of BOC-protection, 3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (100M%) is dissolved among the DMF (20ml), disposable adding NaH (95%, 100M%).This reaction mixture was stirred 1 hour.Add methyl-iodide (300M%), this mixture was stirred 12 hours.Then this reactant is inclined to water, with ethyl acetate (3 *) extraction.Water (3 *) and salt solution (1 *) back scrubbing then.With sal epsom processing, rotary evaporation and chromatography (5% ethanol/methylene wash-out), obtain the 3-amino-1 of BOC-protection, 5-dimethyl-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone, yield 75%.

Step D: with the 3-amino-1 of BOC-protection, 5-dimethyl-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (100M%) is suspended in methylene dichloride/trifluoroacetic acid of 1: 1 of 30ml.Above-mentioned reaction mixture was stirred 4 hours.The rotary evaporation reactant obtains 3-amino-1 then, 5-dimethyl-1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone (100% yield).

Embodiment 6-B

5-(L-alanyl)-amino-3,3,7-trimethylammonium-5,7-dihydro-6H-

Synthesizing of benzo [b] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-I, with 5-amino-3,3,7-trimethylammonium-5,7-dihydro-6H-benzo [b] azatropylidene-6-keto hydrochloride (embodiment 6-C), preparation title compound.

Embodiment 6-C

5-amino-3,3,7-trimethylammonium-5,7-dihydro-6H-benzo [b] azatropylidene-

Synthesizing of 6-keto hydrochloride

Steps A: according to universal method 5-A; with N-t-Boc-5-amino-3; 3-dimethyl-5; 7-dihydro-6H-benzo [b] azatropylidene-6-ketone (universal method 6-B; protect with Boc then) and methyl-iodide, preparation N-t-Boc-5-amino-3,3; 7-trimethylammonium-5,7-dihydro-6H-benzo [b] azatropylidene-6-ketone.

Step B: according to universal method 8-N, with N-t-Boc-5-amino-3,3,7-trimethylammonium-5,7-dihydro-6H-benzo [b] azatropylidene-6-ketone, preparation title compound.

Embodiment 6-D

3-(S)-amino-1-methyl-5-oxa--1,3,4,5-tetrahydrochysene-2H-1-

Synthesizing of benzo-aza -2-ketone

Steps A: adopt R.J.DeVita etc., Bioorganic and Medicinal ChemistryLett.1995, the method of 5 (12) 1281-1286, with N-Boc-Serine (Bachem) and 2-fluoro-1-oil of mirbane (Aldrich), preparation 3-(S)-amino-5-oxa--1,3,4,5-tetrahydrochysene-2H-1-benzo-aza -2-ketone.

Step B: according to universal method 5-A, with the product that derives from steps A, the preparation title compound.

Embodiment 6-E

3-(S)-amino-1-ethyl-5-oxa--1,3,4,5-tetrahydrochysene-2H-1-

Synthesizing of benzo-aza -2-ketone

Embodiment 6-F

3-(S)-amino-1-methyl-5-thia-1,3,4,5-tetrahydrochysene-2H-1-

Synthesizing of benzo-aza -2-ketone

Adopt R.J.DeVita etc., Bioorganic and Medicinal Chemistry Lett.1995, the method for 5 (12) 1281-1286 is then according to universal method 5-A, with N-Boc-Gelucystine (Novabio) and 2-fluoro-1-oil of mirbane (Aldrich), the preparation title compound.

Universal method 7-A

5-amino-7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-

The preparation of 6-ketone derivatives

Steps A: according to universal method 5-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone and alkylogen, preparation 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step B: with 7-alkyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1eq.) is dissolved among the THF, adds Isopentyl nitrite (1.2eq.).This mixture is cooled to 0 ℃ in ice bath.Drip NaHMDS (1.1eq., the THF solution of 1M), stirred 1 hour or after question response finishes, this mixture is concentrated and use the 1N hcl acidifying, use ethyl acetate extraction.Dry also the concentrating of above-mentioned organic moiety obtained the crude product product, and it is used the silica gel column chromatography purifying.

Step C: the gained oxime is dissolved in methyl alcohol/ammonia (20: 1), and in 100 ℃, pressure pan (bomb), with Raney nickel and hydrogen (500psi) hydrogenation 10 hours.The gained mixture filtered and concentrate obtain oily matter, obtain title compound through the silica gel column chromatography purifying.

Universal method 7-B

5 of fluorine replacement, the preparation of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone derivatives

Adopt Robin D.Clark and Jahangir, Tetrahedron, the 49th rolls up improving one's methods of the 7th phase 1351-1356 page or leaf (1993).Specifically, N-t-Boc-2-amino-the 2 '-methyl diphenyl that suitably replaces is dissolved among the THF, and is cooled to-78 ℃.(cyclohexane solution of 1.3M 2.2eq.), keeps temperature to be lower than-65 ℃ slowly to add s-butyl lithium.To-25 ℃, stirring is 1 hour under room temperature with the mixture temperature that produces.This mixture is cooled to-78 ℃.In this mixture, fed dry carbonic acid gas 30 seconds.With this mixture temperature to room temperature, careful then water quencher.This mixture of concentrating under reduced pressure transfers to 3 with 1N hydrochloric acid with pH then.With this mixture of ethyl acetate extraction, dry organic moiety, and the concentrated crude product material that obtains.This crude product material is dissolved in the methyl alcohol, makes this solution saturated with HCl.In refluxing down, cool off then this mixture heating up 12 hours.Concentrate this mixture, obtain the crude product lactan, with it through chromatography or crystallization purifying.

Universal method 7-C

5-amino-7-methyl-5, the fractionation of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone

In round-bottomed flask, add the racemize free alkali amine (1.0eq.) in the methyl alcohol, then add two-right-toluyl-D-tartrate monohydrate (1.0eq.).This mixture of vacuum concentration obtains residue, it is dissolved in the methyl alcohol of proper volume again, and in room temperature, be exposed under this environment and stir (8-72 hour).Filter and take out solid.Measure enantiomeric excess through chirality HPLC (Chiracel ODR), with 15% acetonitrile and 85% water elution that contain 0.1% trifluoroacetic acid, flow velocity is 1.0ml/min in the time of 35 ℃.Two-right-toluyl-D-the tartrate that will split then is dissolved in ethyl acetate and the saturated sodium bicarbonate, to pH be 9-10.Separate each layer, with saturated sodium bicarbonate, water and salt water washing organic layer.Through the dried over mgso organic layer, filter and remove siccative.Vacuum concentrated filtrate.Unhindered amina is dissolved in the methyl alcohol, and adding hydrochloric acid (12M, 1.0eq.).This salt of vacuum concentration grinds the membranoid substance that produces with ethyl acetate.The filter salts hydrochlorate is used ethyl acetate rinse.Measure ee through chirality HPLC.

Embodiment 7-A

5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-

Synthesizing of 6-keto hydrochloride

Steps A: 7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

In round-bottomed flask, be added in the sodium hydride (0.295g among the 9.0ml DMF, 7.46mmol), with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1.3g, 6.22mmol) (CAS# 20011-90-9 prepares described in Tetrahedron Letters the 8th phase 667-670 page or leaf (1971) and the document quoted from according to Brown etc.) handle.After 1 hour, (1.16ml 18.6mmol) handles this solution, and continues to stir 17 hours under lucifuge with methyl-iodide in 60 ℃ of stirrings.After the cooling, dilute this reactant, with sodium bisulfate and water washing, through dried over sodium sulfate with methylene dichloride/water.Evaporation and flash chromatography (silicon-dioxide is used the chloroform wash-out) obtain 0.885g (63%) and are the title compound of colorless solid.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.62(d，2H)，7.26-7.47(m，6H)，3.51(m，2H)，3.32(s，3H)。

C ₁₅H ₁₃NO (MW=223.27), mass spectrum (MH ⁺) 223.

C ₁₅H ₁₃NO analytical calculation value: C, 80.69; H, 5.87; N, 6.27.Measured value: C, 80.11; H, 5.95; N, 6.23.

Step B:7-methyl-5-oximido-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

(0.700g 3.14mmol) is dissolved in the toluene of 20ml the compound that above-mentioned separation is obtained, and (0.733ml 6.28mmol) handles with butyl nitrite.Temperature of charge is reduced to 0 ℃, and under nitrogen atmosphere, (9.42ml handles 0.5M) with KHMDS with this solution.Stir after 1 hour, this reactant with saturated sodium bisulfate quencher, is diluted and separation with methylene dichloride.Use the dried over sodium sulfate organic layer, what chromatography (silicon-dioxide, 98: 2 chloroform/methanol are eluent) purifying obtained 0.59g (80%) is the title compound of colorless solid.

C ₁₅H ₁₂N ₂O ₂(MW=252.275), mass spectrum (MH ⁺) 252.

C ₁₅H ₁₂N ₂O ₂Analytical calculation value: C, 71.42; H, 4.79; N, 11.10.Measured value: C, 71.24; H, 4.69; N, 10.87.

Step C:5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride synthetic

In Parr equipment, under the 35psi, (0.99g is 3.92mmol) with the 3A ethanolic soln hydrogenation of 10%Pd/C (0.46g) for the oxime that above-mentioned separation is obtained.After 32 hours, this reaction mixture is filtered by Celite pad, filtrate is evaporated to spumescence, and handles with the saturated diethyl ether solution of HCl (g).The gained colorless solid is filtered, obtain the title compound of 0.66g (61%) with cold diethyl ether flushing and vacuum-drying.

The NMR data are as follows:

¹H-nmr(DMSOd ₆)：δ＝9.11(bs，3H)，7.78-7.41(m，8H)，4.83(s，1H)，3.25(s，3H)。

C ₁₅H ₁₄N ₂OHCl (MW=274.753), mass spectrum (MH ⁺Free alkali) 238.

C ₁₅H ₁₄N ₂OHCl analytical calculation value: C, 65.57; H, 5.50; N, 10.19.Measured value: C, 65.27; H, 5.67; N, 10.13.

Embodiment 7-B

(S)-and (R)-5-(L-alanyl)-amino-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-ketone

Steps A: (S)-and (R)-5-(N-Boc-L-alanyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

(0.429g, 2.26mmol Aldrich) are dissolved among the THF with the Boc-L-L-Ala, and with the HOBt hydrate (0.305g, 2.26mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (0.45g, 1.89mmol, embodiment 7-A) processing.Cool the temperature to 0 ℃, and (0.449g, 2.26mmol Aldrich) handle above-mentioned reaction mixture, stir 17 hours down in nitrogen with EDC.With this reaction mixture evaporation, residue is with ethyl acetate/water dilution, with 1.0N hydrochloric acid, saturated sodium bicarbonate, salt water washing, dried over sodium sulfate.Separate diastereomer through Chiralcel OD post (using the 10%IPA/ heptane) with 1.5ml/min speed wash-out.

Isomer 1: retention time is 3.37 minutes.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.62-7.33(m，9H)，5.26(d，1H)，5.08(m，1H)，4.34(m，1H)，3.35(s，3H)，1.49(s，9H)，1.40(d，3H)。

Specific rotation: [α] ₂₀=-96 in the 589nm place (c=1, methyl alcohol).

C ₂₃H ₂₇N ₃O ₄(MW=409.489); Mass spectrum (MH ⁺) 409.

C ₂₃H ₂₇N ₃O ₄Analytical calculation value: C, 67.46; H, 6.64; N, 10.26.Measured value: C, 68.42; H, 7.02; N, 9.81.

Isomer 2: retention time is 6.08 minutes.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝7.74(bd，1H)，7.62-7.32(m，8H)，5.28(d，1H)，4.99(m，1H)，4.36(m，1H)，3.35(s，3H)，1.49(s，9H)，1.46(d，3H)。

Specific rotation: [α] ₂₀=69 in the 589nm place (c=1, methyl alcohol).

C ₂₃H ₂₇N ₃O ₄(MW=409.489); Mass spectrum (MH ⁺) 409.

C ₂₃H ₂₇N ₃O ₄Analytical calculation value: C, 67.46; H, 6.64; N, 10.26.Measured value: C, 67.40; H, 6.62; N, 10.02.

Step B:(S)-and (R)-and 5-(L-alanyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride synthetic

Be dissolved in the diox separating the compound (each isomer respectively) that obtains in the part A, and handle with excessive HCl (g).Stir after 17 hours, separate the title compound that obtains to colorless solid after evaporation and the vacuum-drying.

Isomer 1:

C ₁₈H ₁₉N ₃O ₂.HCl (MW=345.832); Mass spectrum (MH ⁺Free alkali) 309.

Specific rotation: [α] ₂₀=-55 in the 589nm place (c=1, methyl alcohol).

Isomer 2:

Specific rotation: [α] ₂₀=80 in the 589nm place (c=1, methyl alcohol).

Embodiment 7-C

(S)-and (R)-5-(L-is valyl)-amino-7-methyl-5, the 7-dihydro-

Synthesizing of 6H-dibenzo [b, d] azatropylidene-6-ketone

Steps A: (S)-and (R)-5-(N-Boc-L-is valyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

With Boc-L-Xie Ansuan (0.656g, 3.02mmol, Aldrich) be dissolved among the THF, and with the HOBt hydrate (0.408g, 3.02mmol), Dipea (1.05ml, 6.05mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride (0.75g, 2.75mmol, embodiment 7-A) processing.Cool the temperature to 0 ℃, and (0.601g, 3.02mmol Aldrich) handle above-mentioned reaction mixture, stir 17 hours down in nitrogen with EDC.With this reaction mixture evaporation, residue is with ethyl acetate/water dilution, with 1.0N hydrochloric acid, saturated sodium bicarbonate, salt water washing, dried over sodium sulfate.Separate diastereomer through Chiralcel OD post (using the 10%IPA/ heptane) with 1.5ml/min speed wash-out.

Isomer 1: retention time is 3.23 minutes.

Specific rotation: [α] ₂₀=-120 in the 589nm place (c=1, methyl alcohol).

C ₂₅H ₃₁N ₃O ₄(MW=437.544); Mass spectrum (MH ⁺) 438.

Isomer 2: retention time is 6.64 minutes.

Specific rotation: [α] ₂₀=50 in the 589nm place (c=1, methyl alcohol).

C ₂₅H ₃₁N ₃O ₄(MW=437.544); Mass spectrum (MH ⁺) 438.

Step B:(S)-and (R)-and 5-(L-is valyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride synthetic

Isomer 1:

C ₂₀H ₂₃N ₃O ₂HCl (MW=373.88); Mass spectrum (MH ⁺Free alkali) 338.

Specific rotation: [α] ₂₀=-38 in the 589nm place (c=1, methyl alcohol).

Isomer 2:

Specific rotation: [α] ₂₀=97 in the 589nm place (c=1, methyl alcohol).

Embodiment 7-D

(S)-and (R)-5-(L-tert-leucine)-amino-7-methyl-5, the 7-dihydro-

Synthesizing of 6H-dibenzo [b, d] azatropylidene-6-ketone

Steps A: (S)-and (R)-5-(N-Boc-L-tert-leucyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

With Boc-L-tert-leucine (0.698g, 3.02mmol, Fluka) be dissolved among the THF, and with the HOBt hydrate (0.408g, 3.02mmol), Dipea (1.05ml, 6.05mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride (0.75g, 2.75mmol, embodiment 7-A) processing.Cool the temperature to 0 ℃, and (0.601g, 3.02mmol Aldrich) handle above-mentioned reaction mixture, stir 17 hours down in nitrogen with EDC.With this reaction mixture evaporation, residue is with ethyl acetate/water dilution, with 1.0N hydrochloric acid, saturated sodium bicarbonate, salt water washing, dried over sodium sulfate.Separate diastereomer through Chiralcel OD post (using the 10%IPA/ heptane) with 1.5ml/min speed wash-out.

Isomer 1: retention time is 3.28 minutes.

Specific rotation: [α] ₂₀=-128 in the 589nm place (c=1, methyl alcohol).

C ₂₆H ₃₃N ₃O ₄(MW=451.571); Mass spectrum (MH ⁺) 452.

Isomer 2: retention time is 5.52 minutes.

Specific rotation: [α] ₂₀=26 in the 589nm place (c=1, methyl alcohol).

C ₂₆H ₃₃N ₃O ₃(MW=451.571); Mass spectrum (MH ⁺) 452.

Step B:(S)-and (R)-and 5-(L-tert leucyl)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride synthetic

Be dissolved in the diox separating the compound (each and structure body are respectively) that obtains in the part A, and handle with excessive HCl (g).Stir after 17 hours, separate the title compound that obtains to colorless solid after evaporation and the vacuum-drying.

Isomer 1:

C ₂₁H ₂₅N ₃O ₂.HCl (MW=387.91); Mass spectrum (MH ⁺Free alkali) 352.

Specific rotation: [α] ₂₀=-34 in the 589nm place (c=1, methyl alcohol).

Isomer 2:

Specific rotation: [α] ₂₀=108 in the 589nm place (c=1, methyl alcohol).

Embodiment 7-E

5-(N-Boc-amino)-5,7-dihydro-6H, 7H-dibenzo [b, d] azatropylidene-6-ketone synthetic

Steps A: 5-iodo-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

In-15 ℃, methylene dichloride, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1.0g, 4.77mmol, embodiment 7-A) and Et ₃N (2.66ml, solution stirring 19.12mmol) 5.0 minutes, and with TMSI (1.36ml 9.54mmol) handles.Stir after 15 minutes, once amount add iodine (1.81g, 7.16mmol), with this reactant temperature to 5-10 ℃ and kept 3 hours., dilute and separation the reactant quencher with saturated sodium sulfite with methylene dichloride.Wash this organic layer with S-WAT and sodium bisulfite, use dried over mgso.After the filtration, this organic layer is concentrated into about 20ml, with other 20ml hexane dilution.Filtering separation obtains being the sedimentary title compound of brown.

Step B:5-azido--5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

Above-mentioned isolating iodide are dissolved among the DMF, handle with 1.2 normal sodiumazide.After 17 hours, dilute this mixture in 23 ℃ of stirrings, separate, use the salt water washing, through dried over mgso with ethyl acetate/water.Grind title compound with hot ethyl acetate, be brown powder.

Step C:5-(N-Boc-amino)-5,7-dihydro-6H, 7H-dibenzo [b, d] azatropylidene-6-ketone synthetic

Described trinitride is dissolved in the THF/ water, in the presence of 3.0 normal triphenyl phosphines, stirred 17 hours in 23 ℃.With this reactant of 50% acetate/dilution with toluene, separate, use the toluene aqueous layer extracted, evaporation obtains the oily residue.Add 1N sodium hydroxide pH is transferred to 7.0, collect the acetate that produces, vacuum-drying.At last, handle this compound with Boc acid anhydrides among the THF (1.05 equivalent) and triethylamine (2.1 equivalent).After 5 hours, filter this reactant in 23 ℃ of stirrings, be separated into the title compound of colourless powder.

Embodiment 7-F

5-amino-7-(2-methyl-propyl)-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Steps A: 5-(N-Boc-amino)-7-(2-methyl-propyl)-5, the 7-dihydro-

Synthesizing of 6H-dibenzo [b, d] azatropylidene-6-ketone

With 5-(N-Boc-amino)-5, (0.22g 0.687mmol) handles the DMF solution of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (0.2g, 0.617mmol, embodiment 7-E), and temperature is to 60 ℃ with cesium carbonate.(0.078ml 0.678mmol), and continues to stir 17 hours to add 1-iodo-2-methylpropane in this reaction mixture.After being cooled to 23 ℃, this mixture is diluted with methylene dichloride, with several parts of salt water washings and use dried over sodium sulfate.Title compound is through chromatography (silicon-dioxide, chloroform/methanol are eluent at 9: 1) purifying.

C ₂₃H ₂₈N ₂O ₃(MW=380.41); Mass spectrum (MH ⁺) 381.

C ₂₃H ₂₈N ₂O ₃Analytical calculation value: C, 72.61; H, 7.42; N, 7.36.Measured value: C, 72.31 H, 7.64; N, 7.17.

Step B:5-amino-7-(2-methyl-propyl)-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

In with the saturated De diox of gas HCl, go separate the compound that obtains in the part A to protection.Through evaporation and vacuum-drying, separate obtaining being light color solid title compound.

Embodiment 7-G

5-amino-7-(methoxyl group ethanoyl)-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-

Synthesizing of 6-keto hydrochloride

Steps A: 5-(N-Boc-amino)-7-(methoxyl group ethanoyl)-5, the 7-dihydro-

Synthesizing of 6H-dibenzo [b, d] azatropylidene-6-ketone

With 5-(N-Boc-amino)-5, (1.10g 3.39mmol) handles the DMF solution of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1.03g, 3.08mmol, embodiment 7-E), and temperature is to 60 ℃ with cesium carbonate.(0.321ml, 3.39mmol Aldrich), and continue to stir 17 hours to add acetate bromo methyl esters in this reaction mixture.After being cooled to 23 ℃, this mixture is diluted with methylene dichloride, with several parts of salt water washings and use dried over sodium sulfate.Title compound is through chromatography (silicon-dioxide, chloroform are eluent) purifying.

C ₂₂H ₂₄N ₂O ₅(MW=396.44); Mass spectrum (MH ⁺) 397.

C ₂₂H ₂₄N ₂O ₅Analytical calculation value: C, 66.65; H, 6.10; N, 7.07.Measured value: C, 66.28 H, 5.72; N, 6.50.

Step B:5-amino-7-(methoxyl group ethanoyl)-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

In with the saturated De diox of gas HCl, go separate the compound that obtains in the part A to protection.Through evaporation and vacuum-drying, separate the title compound that obtains to colorless solid.

C ₁₇H ₁₆N ₂O ₃HCl (MW=332.78); Mass spectrum (MH ⁺Free alkali) 297.

Embodiment 7-H

5-amino-7-(3,3-dimethyl-2-butyryl radicals)-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Steps A: 5-(N-Boc-amino)-7-(3,3-dimethyl-butyryl radicals)-5, the 7-dihydro-

Synthesizing of 6H-dibenzo [b, d] azatropylidene-6-ketone

With 5-(N-Boc-amino)-5, (0.3g 0.925mmol) handles the DMF solution of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (0.2g, 0.617mmol, embodiment 7-E), and temperature is to 60 ℃ with cesium carbonate.Add 1-chloro-3 in this reaction mixture, (0.096ml, 0.74mmol Aldrich), and continue to stir 17 hours 3-dimethyl-2-butanone.After being cooled to 23 ℃, this mixture is diluted with methylene dichloride, with several parts of salt water washings and use dried over sodium sulfate.Separate the title compound that obtains to colorless solid.

C ₂₅H ₃₀N ₂O ₄(MW=422.522); Mass spectrum (MH ⁺) 423.

Step B:5-amino-7-(3,3-dimethyl-2-butyryl radicals)-5,7-dihydro-6H-dibenzo [b, d]

Synthesizing of azatropylidene-6-keto hydrochloride

In with the saturated De diox of gas HCl, go separate the compound that obtains in the steps A to protection.Through evaporation and vacuum-drying, separate the title compound that obtains to colorless solid.

Embodiment 7-I

L-alanyl-5-amino-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Steps A: according to universal method III-D, with N-t-Boc-L-L-Ala and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b; d] azatropylidene-6-ketone; preparation N-t-Boc-L-alanyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step B: according to universal method 8-N, adopt N-t-Boc-L-alanyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone, preparation title compound.By this method, also can prepare the N-t-Boc-L-alanyl-5-amino-7-methyl-5 of other replacement, 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Embodiment 7-J

L-is valyl-5-amino-7-methyl-5, and 7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Steps A: according to universal method III-D, with N-t-Boc-L-Xie Ansuan and 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b; d] azatropylidene-6-ketone; the preparation N-t-Boc-L-valyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step B: according to universal method 8-N, adopt N-t-Boc-L-valyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone, preparation title compound.By this method, the N-t-Boc-L-that also can prepare other replacement is valyl-5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Embodiment 7-K

5-amino-7-benzene butyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

According to universal method 7-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone is (with Brown etc., Tetrahedron Letters, No.8,667-670, (1971) and the preparation of the described method of the reference of wherein being quoted) and 1-chloro-4-phenyl butane (Aldrich), prepare title compound.

Embodiment 7-L5-amino-7-cyclopropyl methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

According to universal method 7-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone is (with Brown etc., Tetrahedron Letters, No.8,667-670, (1971) and the preparation of the described method of the reference of wherein being quoted) and (bromomethyl) cyclopropane (Aldrich), prepare title compound.

Embodiment 7-M

5-amino-7-(2 ', 2 ', 2 '-trifluoroethyl)-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-ketone

According to universal method 7-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone is (with Brown etc., Tetrahedron Letters, No.8,667-670, the described method preparation of (1971) and the reference of wherein being quoted) and 1-bromo-2,2,2-Halothane (Aldrich), the preparation title compound.

Embodiment 7-N

5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone synthetic

According to universal method 7-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone is (with Brown etc., Tetrahedron Letters, No.8,667-670, (1971) and the preparation of the described method of the reference of wherein being quoted) and bromocyclohexane (Aldrich), prepare title compound.

Embodiment 7-O

5-(L-alanyl) amino-9-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Step 1: in 78 ℃, THF, 2-bromo-5-toluene fluoride is stirred.Slowly add s-BuLi (1.05eq., the cyclohexane solution of 1.3M), this mixture was stirred 45 minutes.Add trimethyl borate (1.5eq.), and with this mixture temperature to room temperature.Stir after 1 hour, add tetramethyl ethylene ketone (2eq.).Said mixture was stirred 16 hours, and concentrating under reduced pressure.The gained residue is made pulpous state in methylene dichloride, pass through diatomite filtration.Filtrate concentrating obtains oily matter, and chromatography on the silica gel of deactivation (triethylamine wash-out) purifying obtains the boric acid aryl ester.

Step 2: 2-bromo aniline (1eq.) and tert-Butyl dicarbonate (1.1eq.) were stirred 20 hours in 80 ℃.With the cooling of gained mixture, and straight run distillation obtains N-t-Boc-2-bromo aniline under vacuum (house vaccum).

Step 3: under nitrogen, in water/diox of 20%, with N-t-Boc-2-bromo aniline (step 2,1eq.), the boric acid aryl ester (step 1,1.1eq.), K ₂CO ₃(1.1eq.) (0.02eq.) stir with four (triphenyl phosphine) palladium (O).With above-mentioned solution reflux 10 hours.With this mixture cooling and concentrated.The gained residue distributes between water and chloroform.Dry also the concentrating of organic moiety being obtained oily matter, and it is used the silica gel column chromatography purifying, is eluent with 1: 1 dichloromethane/hexane.

Step 4: according to universal method 7-B, with the biphenyl of the replacement that derives from step 3, preparation 9-fluoro-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step 5: in dry DMF, under the room temperature, with 9-fluoro-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1eq., step 4), cesium carbonate (1.1eq., Aldrich) and methyl-iodide (1.1eq. Aldrich) stirred 16 hours.This mixture concentrating under reduced pressure is obtained residue, and it is distributed between ethyl acetate and water.Dry also the concentrating of organic moiety obtained oily matter, and it is used the silica gel column chromatography purifying, obtain 9-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step 6: according to universal method 7-A, step B with derive from the 9-fluoro-7-methyl-5 of step 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone, preparation 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step 7: according to the method for embodiment 7-I, with the 5-amino-9-fluoro-7-methyl-5 that derives from step 6,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone, the preparation title compound.

Embodiment 7-P

5-(L-alanyl) amino-13-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-O, (step 2, Lancaster) (step 3 Aldrich), prepares title compound with o-tolyl boric acid with 2-bromo-4-fluoroaniline.

Embodiment 7-Q

5-(L-alanyl) amino-10-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-O, with 2-bromo-4-toluene fluoride (step 1), preparation title compound.

Embodiment 7-R

5-(L-alanyl)-amino-7-cyclopropyl methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-I, with 5-amino-7-cyclopropyl methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (embodiment 7-L), the preparation title compound.

Embodiment 7-S

5-(L-alanyl)-amino-7-benzene butyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-I, with 5-amino-7-benzene butyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (embodiment 7-K), the preparation title compound.

Embodiment 7-T

5-(L-is valyl) amino-7-cyclopropyl methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-J, with 5-amino-7-cyclopropyl methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (embodiment 7-L), the preparation title compound.

Embodiment 7-U

5-(L-is valyl) amino-7-benzene butyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-J, with 5-amino-7-benzene butyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (embodiment 7-U), the preparation title compound.

Embodiment 7-V

5-(L-is valyl)-amino-7-hexyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

Steps A: according to universal method 7-A, with 5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone is (with Brown etc., Tetrahedron Letters, No.8,667-670, the described method preparation of (1971) and the reference of wherein being quoted) and 1-bromo hexane (Aldrich), preparation 5-amino-7-hexyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone.

Step B: according to the method for embodiment 7-J, with 5-amino-7-hexyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone, the preparation title compound.

Embodiment 7-W

5-(L-is valyl) amino-10-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-J, with 5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (as prepared among the embodiment 7-Q), the preparation title compound.

Embodiment 7-X

5-(L-is valyl) amino-13-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-J, with 5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (as prepared among the embodiment 7-P), the preparation title compound.

Embodiment 7-Y

5-(L-is valyl)-amino-13-fluoro-7-methyl-5,7-dihydro-6H-

Synthesizing of dibenzo [b, d] azatropylidene-6-keto hydrochloride

According to the method for embodiment 7-J, with 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (prepared) as embodiment 7-O, the preparation title compound.

Embodiment 7-Z

(5-amino-7-methyl isophthalic acid, 2,3,4,5,7-six hydrogen-6H-dicyclohexyl [b, d] azatropylidene-

Synthesizing of 6-ketone

With 5-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-6-keto hydrochloride (embodiment 7-A) is dissolved in ethyl acetate/acetate mixture of 1: 1.The Rh/C of adding 5% stirs the hydrogen of this mixture in 60psi down in 60 ℃.After 3 days, this mixture is filtered, filtrate concentrating obtains oily matter, and it is obtained title compound through SCX-cation-exchange chromatography purifying.

Embodiment 7-AA

5-(S)-amino-7-methyl-5,7-dihydro-6H-dibenzo [b, d] azatropylidene-

Synthesizing of 6-keto hydrochloride

According to universal method 7-C; with racemic 5-amino-7-methyl-5; the methanol solution of 7-dihydro-6H-dibenzo [b, d] azatropylidene-6-ketone (1.0eq.) and two-right-toluyl-D-tartrate monohydrate (1.0eq.) is prepared as the solid title compound.Filter and collect product.Measure enantiomeric excess through chirality HPLC.

Required enantiomorph 1: retention time is 9.97 minutes.

Unwanted enantiomorph 2: retention time is 8.62 minutes.

The NMR data are as follows:

¹H-nmr(CDCl ₃)：δ＝9.39(s，2H)，7.75-7.42(m，8H)，4.80(s，1H)，3.30(s，3H)。

C ₁₅H ₁₅ClN ₂O (MW=274.75); Mass spectrum (MH ⁺) 239.1.

C ₁₅H ₁₅ClN ₂O ₃Analytical calculation value: C, 65.57; H, 5.50; N, 10.20.Measured value: C, 65.51; H, 5.61; N, 10.01.

Universal method 8-A

The N-1-of benzodiazepine methylates

In 0 ℃, handle DMF (0.1M concentration) solution of benzodiazepine (1eq.) with potassium tert.-butoxide (1.0eq., the THF solution of 1.0M.).In 0 ℃, stir after 30 minutes, add methyl iodide (1.3eq.), continue to stir 25 minutes.Dilute this mixture with methylene dichloride, water and salt water washing.Through the dried over sodium sulfate organic phase, filter and concentrate.Then through grinding with 1: 1 ether/hexane or through HPLC chromatography (with ethyl acetate/hexane as eluent) purifying crude product product.

Universal method 8-B

Cbz removal method

The amino benzodiazepine (1eq.) of 3-that in flask, adds the Cbz-protection.To wherein adding HBr (34eq., 30% acetic acid solution).In 20 minutes, all raw materials all dissolve.Under room temperature, this reactant was stirred 5 hours.In orange solution, add ether and make HBr amine salt precipitation.Incline and mixture.This is added ether and the process triplicate that of inclining to remove acetate and bromotoluene.Add toluene, this mixture of vacuum concentration.Also repeat this step.HBr salt is allocated between ethyl acetate and the 1M salt of wormwood.With the ethyl acetate water layer of stripping.Organism with the salt water washing merges through dried over sodium sulfate, filters and concentrates.

Universal method 8-C

Boc removal method

Methylene dichloride (0.15M concentration) solution of the amine (1eq.) of Boc-protection is cooled to 0 ℃, handles with trifluoroacetic acid (30eq.).In 0 ℃ after 10 minutes, remove cooling bath, continue to stir 20 minutes to 1 hour in room temperature.This mixture of vacuum concentration is removed excessive trifluoroacetic acid.Residue is dissolved in the methylene dichloride, with saturated sodium bicarbonate or 1M wet chemical and salt water washing.Through the dried over sodium sulfate organic layer, filter and concentrate.

Universal method 8-D

Carry out the trinitride shift reaction with KHMDS

According to John W.Butcher etc. at Tet.Lett., 37, method described in the 6685-6688 (1996), preparation azido-derivative.

Universal method 8-E

Carry out the trinitride shift reaction with LDA

Maintain the temperature at-78 ℃, in being cooled to-78 ℃ the 1ml anhydrous THF solution of diisopropylamine (1.1eq.), drip n-Butyl Lithium (the 1.6M hexane solution, 1.1eq.).In-78 ℃, this reaction mixture was stirred 30 minutes, drip the 1ml anhydrous THF solution of lactan (0.471mM) then.In-78 ℃, this reaction mixture was stirred 30 minutes, add the 1ml anhydrous THF solution of pre-cooled trisyl trinitride (1.2eq.) then.In-78 ℃, this reaction mixture was stirred 20 minutes, use acetate (4.0eq.) quencher then.In 40 ℃ this reaction mixture was stirred 2 hours subsequently.Then this reactant is inclined to ethyl acetate, water, sodium bicarbonate and salt water washing through dried over sodium sulfate, are filtered and are concentrated.Residue is through the LC2000 chromatography purification.

Universal method 8-F

The azido-reduction reaction

According to John W.Butcher etc. at Tet.Lett., 37, method described in the 6685-6688 (1996) is reduced to corresponding primary amines with azido-.

Universal method 8-G

Carry out the N-alkylation of acid amides or lactan with sodium hydride or potassium tert.-butoxide

The 10ml DMF solution that in the 15ml dry DMF slurry of sodium hydride or potassium tert.-butoxide (1.1eq.), adds suitable acid amides (0.0042mol).Add alkyl iodide then, produce thick slurry.With the passing of time, reactant is thinning, and when when the TLC monitoring reaction is finished, solution becomes homogeneous.This reaction mixture is inclined to ice, use ethyl acetate extraction.Water and salt solution wash organic layer successively.Through the dried over sodium sulfate organic layer, filter and concentrating under reduced pressure then.Residue is through HPLC (LC 2000) purifying, with ethyl acetate/hexane eluent system wash-out.

Universal method 8-H

Carry out the N-alkylation of acid amides or lactan with KHMDS

In the THF solution that is cooled to-78 ℃ suitable acid amides or lactan, drip KHMDS,, this reaction mixture was stirred 30 minutes in-78 ℃.Maintain the temperature at-70 ℃ then and drip alkyl iodide.Remove cooling bath, make reactant rise to room temperature, continue to stir 2 hours.Subsequently this reaction mixture is inclined to ice, use ethyl acetate extraction.Water and salt solution wash organic extract successively.Through the dried over sodium sulfate organic layer, filter and concentrating under reduced pressure then.Residue is through HPLC (LC 2000) purifying, with ethyl acetate/hexane eluent system wash-out.

Universal method 8-I

Carry out the N-alkylation of acid amides or lactan with cesium carbonate

In the DMF of acid amides or lactan solution, add cesium carbonate (1.05eq.) and alkyl iodide (1.1eq.).Under room temperature, this mixture stirring is spent the night, use the ethyl acetate diluted reaction mixture then, water and salt solution wash successively.Through the dried over sodium sulfate organic layer, filter and concentrating under reduced pressure then.Residue is through HPLC (LC 2000) purifying, with ethyl acetate/hexane eluent system wash-out.

Universal method 8-J

BOC removal method

Under room temperature, in the compound of N-Boc protection, add methylene dichloride/trifluoroacetic acid (4: 1).Under room temperature, this reaction mixture was stirred 3 hours, concentrate then.Use the dichloromethane extraction residue, water and saturated sodium bicarbonate washing through dried over sodium sulfate, are filtered and are concentrated, and obtain unhindered amina.

Universal method 8-K

The trinitride transfer method

According to Evans, D.A.; Britton, T.C.; Ellman, J.A.; Dorow, R.L.J.Am.Chem.Soc.1990,112, this trinitride transfer is carried out in improving one's methods of method described in the 4011-4030.Under-78 ℃, nitrogen, dripped KN (TMS) in the THF to lactan Substrate (1.0eq.) (about 0.1M) solution with 2-10 minute ₂(1.1eq., 0.5M toluene solution Aldrich), can be observed slight exothermic reaction usually through internal thermometer, with solution stirring 5-15 minute that obtains, are cooled to-78 ℃ again.Then by conduit, with THF (about 0.5M) solution under-78 ℃ or the room temperature of being precooled to that added trisyl trinitride (1.1-1.5eq., CAS No.36982-84-0 is according to the described preparation of above-mentioned Evans reference) in 0.5-5 minute.Usually can observe slight exothermic reaction once more.When being cooled to-78 ℃ again, with solution stirring 5-10 minute that produces.Add acetate (4.5-4.6eq, glacial acetic acid) subsequently, remove cooling bath, under agitation, with this mixture temperature to room temperature 12-16 hour.Dilute this mixture with initial THF2-5 volume doubly with ethyl acetate, with dilute aqueous solution of sodium bicarbonate (1-2 *), 0.1-1.0M aqueous hydrochloric acid (0-2 *) and salt solution (1 *) washing, use the dried over mgso organic phase then, filter and concentrate, obtain the crude product product.

Universal method 8-L

Trinitride is reduced to amine

Under room temperature, hydrogen pressure (35-45psi), with the mixture among the dehydrated alcohol (0.03-0.07M) of trinitride and the 10%Pd/C (be about trinitride weight 1/3) on the Parr device jolting 3-6 hour.Filter the removal catalyzer by Celite pad, with the dehydrated alcohol flushing, concentrated filtrate obtains crude product amine product.

Universal method 8-M

Carry out alkylation of amide with cesium carbonate

This method is Claremon, and D.A. etc. apply at PCT: method improves one's methods described in the WO 96-US8400 960603.Under room temperature, nitrogen, to 2,4-dioxo-2,3,4,5-tetrahydrochysene-1H-1, (1.0eq. 0.7M) adds cesium carbonate (2.2eq.) and suitable alkylogen (2.2eq.) to the DMF of 5-benzodiazepine (CAS No.49799-48-6) in the mixed solution.Under room temperature, this mixture was stirred 5.5-16 hour.This mixture is allocated between ethyl acetate and the saturated sodium bicarbonate.With ethyl acetate (1-2 *) aqueous layer extracted, through the acetic acid ethyl ester extract that dried over sodium sulfate merges, filter and concentrate, obtain the crude product product.

Universal method 8-N

BOC removal method

Under nitrogen,, fed the dry hydrogen chloride air-flow 10-15 minute in 4-diox (0.03-0.09M) stirred solution on ice bath, being cooled to the amino acid whose 1 of about 10 ℃ N-t-Boc protection.Seal this solution, remove cooling bath, under agitation make this solution rise to room temperature 2-8 hour, through TLC monitoring consumption of raw materials.Concentrate this solution (be dissolved in it in methylene dichloride in some cases, reconcentration, place vacuum chamber in 60-70 ℃) to remove most of residual De diox, and with it without being further purified use.

Embodiment 8-A

3-amino-1,3-dihydro-5-(piperidino)-2H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 1,2-dihydro-3H-1-methyl-5-(piperidino)-1,4-benzodiazepine -

The preparation of 2-ketone

The dichloromethane solution of phosphorus pentachloride (1.2eq.) is dropped to the 1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-3H-1,4-benzodiazepine -2, the 5-diketone (according to Showell, G.A.; Bourrain, S.; Neduvelil, J.G.; Fletcher, S.R.; Baker, R.; Watt, A.P.; Fletcher, A.E.; Freedman, S.B.; Kemp, J.A.; Marshall, G.R.; Patel, S.; Smith, A.J.; Matassa, V.G. be at J.Med.Chem.1994, preparation described in 37,719) dichloromethane solution in.Under room temperature, with the yellowish-orange solution stirring that produces 2.5 hours, vacuum was removed solvent.Orange residue is dissolved in the methylene dichloride again, is cooled to 0 ℃, handle with the dichloromethane solution of piperidines (2eq.) and triethylamine (2eq.).Remove cooling bath, this reactant was stirred 18 hours.With saturated sodium bicarbonate aqueous solution (using dichloromethane extraction) and this reaction mixture of salt water washing.Through the dried over sodium sulfate organic phase, filter and concentrate.Residue with 4-10% ethanol/methylene gradient elution, obtains the title intermediate into yellow solid through the HPLC purifying, and fusing point is 103-105 ℃.

C ₁₅H ₁₉N ₃O (MW 257.37); Mass spectrum 257.

C ₁₅H ₁₉N ₃O analytical calculation value: C, 70.01; H, 7.44; N, 16.33.Measured value: C, 69.94; H, 7.58; N, 16.23.

Step B:1,2-dihydro-3H-1-methyl-3-oximido-5-(piperidino)-1,4-benzodiazepine

The preparation of -2-ketone

With potassium tert.-butoxide (2.5eq.) divide two portions add to-20 ℃ 1,2-dihydro-3H-1-methyl-5-(piperidino)-1 is in the toluene solution of 4-benzodiazepine -2-ketone (1eq.).In-20 ℃ stir 20 minutes after, in red reaction mixture, add Isopentyl nitrite (1.2eq., Aldrich).In-20 ℃, this reactant to be stirred 5 hours, TLC monitoring this moment shows to react to be finished.Remove cooling bath, with 0.5M citric acid quencher reactant.Stir after 10 minutes, add ether.Under room temperature, this suspension stirring is spent the night, filter then and wash with ether.The cream-colored solid fusing point that produces is 197-200 ℃.

The E/Z isomer ¹H NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.64(1H，bs)，7.48(2H，d，J＝7.4Hz)，7.35-7.20(6H，m)，6.75(1H，bs)，3.8-3.2(8H，m)，3.46(3H，s)，3.42(3H，s)，1.90-1.40(12H，m)。

C ₁₅H ₁₈N ₄O ₂(MW=286.37); Mass spectrum 286.

Step C:1.2-dihydro-3H-1-methyl-3-[O-(B aminocarbonyl) oximido]-5-(1-piperidines

Base)-1, the preparation of 4-benzodiazepine -2-ketone

Handle 1,2-dihydro-3H-1-methyl-3-oximido-5-(piperidino)-1, the THF mixed solution of 4-benzodiazepine -2-ketone (1eq.) with ethyl isocyanate (1.7eq.) and triethylamine (0.6eq.).With this mixture heating up to 64 ℃ 4 hours.Concentrate this mixture, residue is through the HPLC purifying, with 5% ethanol/methylene wash-out.

The E/Z isomer ¹H NMR data are as follows:

¹H?NMR(300MHz，CDCl ₃)：δ＝7.50(2H，dd，J＝8.4，1.5Hz)，7.35-7.22(6H，m)，6.42(1H，bt)，6.20(1H，bt)，3.7-3.4(8H，m)，3.46(3H，s)，3.44(3H，s)，3.25(4H，m)，1.9-1.4(12H，m)，1.12(3H，t，J＝6.3Hz)，1.10(3H，t，J＝6.3Hz)。

C ₁₈H ₂₃N ₅O ₃(MW=357.46); Mass spectrum 357.

Step D:3-amino-1,3-dihydro-2H-1-methyl-5-(piperidino)-1,4-benzodiazepine

The preparation of -2-ketone

In under the 43psi, in methyl alcohol, with 5% palladium charcoal (0.15eq.) with 1,2-dihydro-3H-1-methyl-3-[O-(B aminocarbonyl) oximido]-5-(piperidino)-1,4-benzodiazepine -2-ketone (1eq.) hydrogenation 3.25 hours.By this reactant of diatomite filtration, vacuum concentration.Residue is dissolved in the methylene dichloride, and passes through diatomite filtration once more.Concentrated filtrate uses the foam that produces immediately.

Embodiment 8-B

3-(L-alanyl)-amino-2,3-dihydro-1-methyl-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone, (1S)-7, the preparation of 7-dimethyl-2-oxo dicyclo [2.2.1] heptane-1-methanesulfonates

According to Reider, P.J.; Davis, P.; Hughes, D.L.; Grabowski, E.J.J.J.Org.Chem.1987,52,955 described methods, with 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone is (according to Bock M.G.; DiPardo, R.M.; Evans, B.E.; Rittle, K.E.; Veber, D.F.; Freidinger, R.M.; Hirshfield, J.; Springer, J.P. prepare described in 52,3232 at J.Org.Chem.1987) as raw material, preparation title intermediate.

Step B:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-

Methyl-5-phenyl-1H-1, the preparation of 4-benzodiazepine -2-ketone

By being allocated in methylene dichloride and the 1M salt of wormwood, make (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone, (1S)-7,7-dimethyl-2-oxo dicyclo [2.2.1] heptane-1-methanesulfonates alkali is free.According to universal method III-D, make this unhindered amina and the coupling of N-Boc-L-Ala then.

C ₂₄H ₂₈N ₄O ₄(MW=436.56); Mass spectrum 436.

C ₂₄H ₂₈N ₄O ₄Analytical calculation value: C, 66.03; H, 6.47; N, 12.84.Measured value: C, 65.79; H, 6.68; N, 12.80.

Step C:3-(L-alanyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzene

And the preparation of diaza -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title compound of white foam shape thing.

C ₁₉H ₁₉N ₄O ₂Analytical calculation value: C, 69.21; H, 6.64; N, 15.37.Measured value: C, 70.11; H, 6.85; N, 15.01.

Embodiment 8-C

3-(L-alanyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-(carbobenzoxy)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzene

And the preparation of diaza -2-ketone

With 3-(carbobenzoxy)-amino-7-chloro-2,3-dihydro-5-phenyl-1H-1, (1eq., DMF solution Neosystem) is cooled to 0 ℃ to 4-benzodiazepine -2-ketone, handles with potassium tert.-butoxide (1eq., 1.0MTHF solution).Under 0 ℃, the yellow solution that produces was stirred 30 minutes, use methyl-iodide (1.3eq.) quencher then.Behind the restir 25 minutes, dilute this reactant, water and salt water washing with methylene dichloride.Through the dried over sodium sulfate organic phase, filter and concentrate.Residue is through the HPLC chromatography purification, with the ethyl acetate/hexane gradient elution of 20-30%.

C ₂₄H ₂₀ClN ₃O ₃(MW=433.92); Mass spectrum 433.

C ₂₄H ₂₀ClN ₃O ₃Analytical calculation value: C, 66.44; H, 4.65; N, 9.68.Measured value: C, 66.16; H, 4.50; N, 9.46.

Step B:3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine

The preparation of -2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing, and it is used for step C immediately.

Step C:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-chloro-1, the 3-dihydro

-1-methyl-5-phenyl-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.

C ₂₄H ₂₈ClN ₄O ₄(MW=471.18); Mass spectrum 471.

C ₂₄H ₂₈ClN ₄O ₄Analytical calculation value: C, 61.21; H, 5.78; N, 11.90.Measured value: C, 61.24; H, 5.59; N, 11.67.

Step D:3-(L-alanyl)-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-

1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.This crude product material is used immediately.

Embodiment 8-D

3-(L-alanyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-(carbobenzoxy) amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-

1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy)-amino-7-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone (Neosystem) is prepared as the title intermediate of white foam shape thing.

C ₂₄H ₁₉BrFN ₃O ₃(MW=496.36); Mass spectrum 497.

C ₂₄H ₁₉BrFN ₃O ₃Analytical calculation value: C, 58.08; H, 3.86; N, 8.47.Measured value: C, 57.90; H, 4.15; N, 8.20.

Step B:3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzo two

The preparation of azatropylidene-2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing, and it is used for step C immediately.

Step C:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-bromo-1, the 3-dihydro

-1-methyl-5-(2-fluorophenyl)-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method IIID, with N-Boc-L-Ala (Novo) and 3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.

C ₂₄H ₂₆BrFN ₄O ₄(MW=533.12); Mass spectrum 533.2.

C ₂₄H ₂₆BrFN ₄O ₄Analytical calculation value: C, 54.04; H, 4.91; N, 10.50.Measured value: C, 53.75; H, 4.92; N, 10.41.

Step D:3-(L-alanyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorobenzene

Base)-and 2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.This crude product material is used immediately.

Embodiment 8-E

3-(N '-methyl-L-alanyl)-amino-2,3-dihydro-1-methyl-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-[N '-(t-butyl carbamate)-N '-methyl-L-alanyl]-amino-2,3-

Dihydro-1-methyl-5-phenyl-1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone (embodiment 8-B) and uncle N--Boc-N-methyl-L-Ala (Sigma) obtains the title intermediate into white solid.

C ₂₅H ₃₀N ₄O ₄(MW=450.2); Mass spectrum (M+1) 451.2.

C ₂₅H ₃₀N ₄O ₄Analytical calculation value: C, 66.65; H, 6.71; N, 12.44.Measured value: C, 66.66; H, 6.89; N, 12.21.

Steps A: 3-(N '-methyl-L-alanyl)-amino-2,3-dihydro-1-methyl-5-phenyl-

1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-N '-methyl-L-alanyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.

C ₂₀H ₂₂N ₄O ₂(MW=350.46); Mass spectrum (M+1) 351.4.

C ₂₀H ₂₂N ₄O ₂Analytical calculation value: C, 68.55; H, 6.33; N, 15.99.Measured value: C, 68.36; H, 6.20; N, 15.79.

Embodiment 8-F

3-(L-alanyl) amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-(carbobenzoxy) amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-1H-

1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy) amino-7-chloro-2,3-dihydro-5-(2-chloro-phenyl-)-1H-1,4-benzodiazepine -2-ketone (Neosystem) is prepared as the title intermediate of white solid, and fusing point is 232-233 ℃.

C ₂₄H ₁₉Cl ₂N ₃O ₃(MW=468.36); Mass spectrum 468.

¹H?NMR(300MHz，CDCl ₃)：δ＝7.67(1H，m)，7.52(1H，dd，J＝2.4，8.7Hz)，7.42-7.26(9H，m)，7.07(1H，d，J＝2.4Hz)，6.70(1H，d，J＝8.3Hz)，5.35(1H，d，J＝8.4Hz)，5.14(2H，ABq，J＝19.6Hz)，3.47(3H，s)。

¹³C?NMR(75MHz，CDCl ₃)：δ＝166.66，165.65，155.72，140.52，136.99，136.0，132.87，131.99，131.47，131.40，131.38，131.16，130.54，130.06，128.45，128.08，128.03，127.72，127.22，123.28，122.01，68.95，67.02，35.32。

Step B:3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing, and it is used for step C immediately.

Step C:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-chloro-1, the 3-dihydro

-1-methyl-5-(2-chloro-phenyl-)-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.

C ₂₄H ₂₆Cl ₂N ₄O ₄(MW=505.44); Mass spectrum 505.2.

Step D:3-(L-alanyl)-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorobenzene

Base)-and 2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chloro-phenyl-)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.This crude product material is used immediately.

Embodiment 8-G

3-(L-alanyl) amino-5-cyclohexyl-2,3-dihydro-1-methyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-(carbobenzoxy)-amino-5-cyclohexyl-2,3-dihydro-1-methyl isophthalic acid H-1.4-benzo

The preparation of diaza -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy)-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepine -2-ketone (Neosystem) is prepared as the title intermediate of white solid, and fusing point is 205-206 ℃.

C ₂₄H ₂₇N ₃O ₃(MW=405.54); Mass spectrum 405.

¹H?NMR(300MHz，CDCl ₃)：δ＝7.54(1H，d，J＝7.9Hz)，7.48(1H，d，J＝7.7Hz)，7.36-7.26(7H，m)，6.54(1H，d，J＝8.3Hz)，5.15(1H，d，J＝8.0Hz)，5.09(2H，ABq，J＝17.1Hz)，3.39(3H，s)，2.77(1H，m)，2.01(1H，bd，J＝13.6Hz)，1.85(1H，bd，J＝12.4Hz)，1.68-1.49(4H，m)，1.34-1.02(4H，m)。

Step B:3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine

The preparation of-2-ketone

According to universal method 8-B, with 3-(carbobenzoxy) amino-5-cyclohexyl-2,3-dihydro-1-methyl isophthalic acid H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing, and it is used for step C immediately.

C ₁₆H ₂₁N ₃O (MW+H=272.1763); Mass spectrum 272.1766.

Step C:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-5-cyclohexyl-1,3-

Dihydro-1-methyl-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.

C ₂₄H ₃₄N ₄O ₄(MW=442.62); Mass spectrum (M+H) 443.2.

Step D:3-(L-alanyl)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-

The preparation of benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.This crude product material is used immediately.

C ₁₉H ₂₆N ₄O ₂(M+H=343.2136); Mass spectrum measured value 343.2139.

Embodiment 8-H

3-(L-alanyl) amino-2,3-2 hydrogen-1-methyl-7-nitro-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 2-[N-(α-iprotiazem base)-N '-(carbobenzoxy)-glycyl]-amino-5-nitro

The preparation of benzophenone

With α-(iprotiazem base)-N-(carbobenzoxy) glycine (1eq., according to Zoller, V.; Ben-Ishai, D.Tetrahedron 1975,31,863 described preparations) anhydrous THF solution be cooled to 0 ℃, with oxalyl chloride (1eq.) and 3 DMF processing.After 15 minutes, remove cooling bath in 0 ℃ of stirring, under room temperature, continue to stir 40 minutes.This solution is cooled to 0 ℃ again.By conduit in acyl chlorides, add 2-amino-5-nitro benzophenone (0.9eq., Acros) and the anhydrous THF solution of 4-methylmorpholine (2.0eq.).Remove cooling bath, under room temperature, this reactant was stirred 5 hours.Dilute this reactant with methylene dichloride, with 0.5M citric acid, saturated sodium bicarbonate aqueous solution and salt water washing.Through the dried over sodium sulfate organic phase, filter and concentrate.Crude product with 15 → 20% ethyl acetate/hexane gradient elutions, obtains the canescence foam through preparation property LC2 000 purifying.

C ₂₆H ₂₅N ₃O ₆S (MW=507.61); Mass spectrum measured value 507.9.

C ₂₆H ₂₅N ₃O ₆S analytical calculation value: C, 61.53; H, 4.96; N, 8.28.Measured value: C, 61.70; H, 4.99; N, 8.22.

Step B:2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl]-amino-5-nitro hexichol

The preparation of ketone

In 0 ℃, to 2-[N-(α-iprotiazem base)-N '-(carbobenzoxy)-glycyl]-feed ammonia in the THF solution of amino-5-nitro benzophenone (1eq.).After 35 minutes, add mercury chloride (II) (1.1eq.).Remove ice bath, in this suspension, continue to feed ammonia 4 hours.Stop ventilation, this reactant is continued to stir 16 hours.By this mixture of diatomite filtration, wash with THF.Vacuum concentrated filtrate.The crude product solid is used for step C without being further purified.

Step C:3-(carbobenzoxy)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzo two

The preparation of azatropylidene-2-ketone

Handle 2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl with glacial acetic acid and ammonium acetate (4.7eq.)]-amino-5-nitro benzophenone (1eq.).Under room temperature, this suspension was stirred 21 hours.Behind this reactant of vacuum concentration, residue is allocated between ethyl acetate and the 1N sodium hydroxide.With the ethyl acetate water layer of stripping.Organism with the salt water washing merges through dried over sodium sulfate, filters and concentrates.Residue is through the flash chromatography purifying, with 2-3% Virahol/dichloromethane gradient wash-out.

C ₂₃H ₁₈N ₄O ₅(MW=430.45); Mass spectrum measured value (M+H) 431.2.

C ₂₃H ₁₈N ₄O ₅Analytical calculation value: C, 64.18; H, 4.22; N, 13.02.Measured value: C, 64.39; H, 4.30; N, 13.07.

Step D:3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-

The preparation of benzodiazepine -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.

C ₂₄H ₂₀N ₄O ₅(MW=444.48); Mass spectrum measured value (M+H) 445.2.

C ₂₄H ₂₀N ₄O ₅Analytical calculation value: C, 64.86; H, 4.54; N, 12.60.Measured value: C, 65.07; H, 4.55; N, 12.46.

Step e: 3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepine

The preparation of assorted -2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam, and it is used for step F immediately.

Step F: 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-

Methyl-7-nitro-5-phenyl-1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow solid.

C ₂₄H ₂₇N ₅O ₆(MW=481.56); Mass spectrum measured value (M+H) 482.3.

C ₂₄H ₂₇N ₅O ₆Analytical calculation value: C, 59.88; H, 5.61; N, 14.55.Measured value: C, 60.22; H, 5.75; N, 13.91.

Step G:3-(L-alanyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-

1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.This crude product material is used immediately.

Embodiment 8-I

3-(L-alanyl) amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine

The preparation of -2-ketone

In flask, add 3-(carbobenzoxy)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone (1eq., embodiment 8-D steps A) and 10% palladium charcoal.Add methyl alcohol, this flask is placed under the hydrogen pressure.Reactant was stirred 21 hours.By this mixture of diatomite filtration, use methanol wash.Concentrated filtrate obtains white solid.

C ₁₆H ₁₄FN ₃O (MW=283.33); Mass spectrum measured value (M+H) 284.1.

Step B:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-1,3-dihydro-1-

Methyl-5-(2-fluorophenyl)-2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white solid.

C ₂₄H ₂₇FN ₄O ₄(MW=454.50); Mass spectrum measured value (M+H) 455.4.

C ₂₄H ₂₇FN ₄O ₄Analytical calculation value: C, 63.44; H, 5.95; N, 12.33.Measured value: C, 63.64; H, 6.08; N, 12.16.

Step C:3-(L-alanyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorobenzene

Base)-and 2H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of white foam shape thing.This crude product material is used immediately.

Embodiment 8-J

3-(L-alanyl) amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: the preparation of 2-amino-3 '-fluorine benzophenone

Under nitrogen, the THF solution of 3-bromofluoro benzene (1eq.) is cooled to-78 ℃, handle with tert-butyl lithium (2.05eq., 1.6M pentane solution) with the speed of 40ml/h.Internal temperature is not above-74 ℃.In-78 ℃, this orange solution was stirred 30 minutes, add the THF solution of anthranilo nitrile (0.6eq.) then.With this reactant temperature to 0 ℃, stirred 2 hours.In this mixture, add 3N hydrochloric acid, continue to stir 30 minutes.Dilute this reactant with ethyl acetate, separate each layer.With ethyl acetate water layer is stripped three times.Extract with the salt water washing merges through dried over sodium sulfate, filters and concentrates.Residue is through the HPLC purifying, with 93: 7 hexane/ethyl acetate wash-out.

C ₁₃H ₁₀FNO (MW=215.24); Mass spectrum measured value (M+H) 216.3.

¹H?NMR(300MHz，CDCl ₃)d7.44-7.19(6H，m)，6.74(1H，d，J＝8.0Hz)，6.61(1H，dd，J＝0.94，7.9Hz)，6.10(2H，bs)。

Step B:2-[N-(α-iprotiazem base)-N '-(carbobenzoxy)-glycyl]-amino-3 '-fluorine two

The preparation of benzophenone

With α-(iprotiazem base)-N-(carbobenzoxy) glycine (1eq., according to Zoller, V.; Ben-Ishai, D.Tetrahedron 1975,31,863 described preparations) anhydrous THF solution be cooled to 0 ℃, with oxalyl chloride (1eq.) and 3 DMF processing.After 15 minutes, remove cooling bath in 0 ℃ of stirring, under room temperature, continue to stir 40 minutes.This solution is cooled to 0 ℃ again.The anhydrous THF solution that in acyl chlorides, adds 2-amino-3 '-fluorine benzophenone (0.9eq.) and 4-methylmorpholine (2.0eq.) by conduit.Remove cooling bath, under room temperature, this reactant was stirred 5 hours.Dilute this reactant with methylene dichloride, with 0.5M citric acid, saturated sodium bicarbonate aqueous solution and salt water washing.Through the dried over sodium sulfate organic phase, filter and concentrate.Residue with 15-20% ethyl acetate/hexane gradient elution, obtains the canescence foam through preparation property LC2000 purifying.

C ₂₆H ₂₅N ₂O ₄S (MW=480.60); Mass spectrum measured value (M+NH ₄ ⁺) 498.3.

¹H?NMR(300MHz，CDCl ₃)d11.39(1H，s)，8.59(1H，d，J＝6.0Hz)，7.63-7.55(2H，m)，7.48-7.27(9H，m)，7.14(1H，dt，J＝1.2，8.4Hz)，5.94(1H，d，J＝7.2Hz)，5.58(1H，d，J＝8.7Hz)，5.17(2H，ABq，J＝14.7Hz)，3.25(1H，sep，J＝6.6Hz)，1.44(3H，d，J＝6.0Hz)，1.28(3H，d，J＝6.6Hz)。

Step C:2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl]-amino-3 '-fluorine benzophenone

Preparation

In 0 ℃, to 2-[N-(α-iprotiazem base)-N '-(carbobenzoxy)-glycyl]-feed ammonia in the THF solution of amino-3 '-fluorine benzophenone (1eq.).After 35 minutes, add mercury chloride (II) (1.1eq.).Remove ice bath, in this suspension, continue to feed ammonia 4 hours.Stop ventilation, this reactant is continued to stir 16 hours.By this mixture of diatomite filtration, wash with THF.Vacuum concentrated filtrate.The crude product solid is used for step D without being further purified.

Step D:3-(carbobenzoxy)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepine

The preparation of assorted -2-ketone

Handle 2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl with glacial acetic acid and ammonium acetate (4.7eq.)]-amino-3 '-fluorine benzophenone (1eq.).Under room temperature, this suspension was stirred 21 hours.Behind this reactant of vacuum concentration, residue is allocated between ethyl acetate and the 1N sodium hydroxide.With the ethyl acetate water layer of stripping.Organism with the salt water washing merges through dried over sodium sulfate, filters and concentrates.Residue is through the flash chromatography purifying, with 2-3% Virahol/dichloromethane gradient wash-out.

C ₂₃H ₁₈FN ₃O ₃(MW=403.44); Mass spectrum measured value (M+H) 404.4.

C ₂₃H ₁₈FN ₃O ₃0.5H ₂O analytical calculation value: C, 66.98; H, 4.64; N, 10.18.Measured value: C, 67.20; H, 4.64; N, 9.77.

Step e: 3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-

The preparation of benzodiazepine -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.

C ₂₄H ₂₀FN ₃O ₃(MW=417.47); Mass spectrum measured value (M+H) 418.3.

C ₂₄H ₂₀FN ₃O ₃Analytical calculation value: C, 69.06; H, 4.83; N, 10.07.Measured value: C, 69.33; H, 4.95; N, 9.82.

Step F: 3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepine

The preparation of -2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam, and it is used for step G immediately.

Step G:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-

Methyl-5-(3-fluorophenyl)-1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method III-D, with N-Boc-L-L-Ala and 3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow solid.

C ₂₄H ₂₇FN ₄O ₄(MW=454.50); Mass spectrum measured value (M+H) 455.3.

C ₂₄H ₂₇FN ₄O ₄Analytical calculation value: C, 63.42; H, 5.99; N, 12.33.Measured value: C, 63.34; H, 6.01; N, 12.08.

Step H:3-(L-alanyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-

1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.This crude product material is used immediately.

Embodiment 8-K

3-(L-alanyl) amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: the preparation of 2-amino-4 '-fluorine benzophenone

Under nitrogen, the THF solution of 4-bromofluoro benzene (1eq.) is cooled to-78 ℃, handle with tert-butyl lithium (2.05eq., 1.6M pentane solution) with the speed of 40ml/h.Internal temperature does not surpass-74C.In-78 ℃, this orange solution was stirred 30 minutes, add the THF solution of anthranilo nitrile (0.6eq.) then.With this reactant temperature to 0 ℃, stirred 2 hours.In this mixture, add 3N hydrochloric acid, continue to stir 30 minutes.Dilute this reactant with ethyl acetate, separate each layer.With ethyl acetate water layer is stripped three times.Extract with the salt water washing merges through dried over sodium sulfate, filters and concentrates.Residue is through the HPLC purifying, with 93: 7 hexane/ethyl acetate wash-out.

C ₁₃H ₁₀FNO (MW=215.24); Mass spectrum measured value (M+H) 216.3.

C ₁₃H ₁₀FNO analytical calculation value: C, 72.55; H, 4.68; N, 6.51.Measured value: C, 72.80; H, 4.51; N, 6.74.

Step B:2-[N-(α-iprotiazem base)-N '-(carbobenzoxy)-glycyl]-amino-4 '-fluorine two

The preparation of benzophenone

With α-(iprotiazem base)-N-(carbobenzoxy) glycine (1eq., according to Zoller, V.; Ben-Ishai, D.Tetrahedron 1975,31,863 described preparations) anhydrous THF solution be cooled to 0 ℃, with oxalyl chloride (1eq.) and 3 DMF processing.After 15 minutes, remove cooling bath in 0 ℃ of stirring, under room temperature, continue to stir 40 minutes.This solution is cooled to 0 ℃ again.The anhydrous THF solution that in acyl chlorides, adds 2-amino-4 '-fluorine benzophenone (0.9eq.) and 4-methylmorpholine (2.0eq.) by conduit.Remove cooling bath, under room temperature, this reactant was stirred 5 hours.Dilute this reactant with methylene dichloride, with 0.5M citric acid, saturated sodium bicarbonate aqueous solution and salt water washing.Through the dried over sodium sulfate organic phase, filter and concentrate.Residue with 15-20% ethyl acetate/hexane gradient elution, obtains the canescence foam through preparation property LC2000 purifying.

C ₂₆H ₂₅N ₂O ₄S (MW=480.60); Mass spectrum measured value (M+NH ₄ ⁺) 498.2.

¹H?NMR(300MHz，CDCl ₃)d11.28(1H，s)，8.56(1H，d，J＝8.4Hz)，7.78-7.73(2H，m)，7.61-7.53(2H，m)，7.36-7.32(5H，m)，7.20-7.14(3H，m)，5.98(1H，d，J＝7.5Hz)，5.57(1H，d，J＝7.8Hz)，5.16(2H，ABq，J＝14.7Hz)，3.25(1H，sep，J＝6.0Hz)，1.43(3H，d，J＝6.3Hz)，1.27(3H，d，J＝6.6Hz)。

Step C:2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl]-amino-4 '-fluorine benzophenone

Preparation

Step D:3-(carbobenzoxy)-amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepine

The preparation of assorted -2-ketone

Handle 2-[N-(alpha-amino group)-N '-(carbobenzoxy)-glycyl with glacial acetic acid and ammonium acetate (4.7eq.)]-amino-4 '-fluorine benzophenone (1eq.).Under room temperature, this suspension was stirred 21 hours.Behind this reactant of vacuum concentration, residue is allocated between ethyl acetate and the 1N sodium hydroxide.With the ethyl acetate water layer of stripping.Organism with the salt water washing merges through dried over sodium sulfate, filters and concentrates.Residue is through the flash chromatography purifying, with 2-3% Virahol/dichloromethane gradient wash-out.

C ₂₃H ₁₈FN ₃O ₃1.25H ₂O analytical calculation value: C, 64.85; H, 4.85.Measured value: C, 64.80; H, 4.55.

Step e: 3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-

The preparation of benzodiazepine -2-ketone

According to universal method 8-A, with 3-(carbobenzoxy)-amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.

C ₂₄H ₂₀FN ₃O ₃(MW=417.47); Mass spectrum measured value (M+H) 418.2.

C ₂₄H ₂₀FN ₃O ₃Analytical calculation value: C, 69.06; H, 4.83; N, 10.07.Measured value: C, 69.35; H, 4.93; N, 9.97.

Step F: 3-amino-1,3-dihydro-1-methyl-5-(4-fluorophenyl)-2H-1,4-benzodiazepine

The preparation of -2-ketone

According to universal method 8-B, with 3-(carbobenzoxy)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam, and it is used for step G immediately.

Step G:3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-

Methyl-5-(3-fluorophenyl)-1H-1, the preparation of 4-benzodiazepine -2-ketone

C ₂₄H ₂₇FN ₄O ₄(MW=454.50); Mass spectrum (M+H) 455.4.

C ₂₄H ₂₇FN ₄O ₄1.5H ₂O analytical calculation value: C, 59.86; H, 6.28; N, 11.64.Measured value: C, 60.04; H, 5.62; N, 11.27.

Step H:3-(L-alanyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-

1H-1, the preparation of 4-benzodiazepine -2-ketone

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-alanyl]-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepine -2-ketone is prepared as the title intermediate of yellow foam.The crude product material is directly used.

Embodiment 8-L

3-(N '-the L-alanyl) amino-2,3-dihydro-1-isobutyl--5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: according to universal method 8-G, make 1 with isobutyl iodide, 3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-ketone is (according to M.G.Bock etc. at J.Org.Chem.1987,52, the preparation of method described in the 3232-3239) alkylation, obtain 1,3-dihydro-1-isobutyl--5-phenyl-2H-1,4-benzodiazepine -2-ketone.

Step B: according to universal method 8-D and 8-F, with the product of steps A, preparation 3-amino-1,3-dihydro-1-isobutyl--5-phenyl-2H-1,4-benzodiazepine -2-ketone.

Step C:, make product and N-Boc-L-L-Ala (Sigma) coupling of step B, subsequently according to universal method 8-J according to universal method III-D; remove the Boc group; it is amino-1 to obtain 3-(N '-L-alanyl), 3-dihydro-1-isobutyl--5-phenyl-2H-1,4-benzodiazepine -2-ketone.

In above-mentioned steps A, replace isobutyl iodide with isopropyl iodide, n-propyl iodide, cyclopropyl methyl-iodide and iodoethane respectively, prepare following other intermediate:

3-(N '-the L-alanyl) amino-1,3-dihydro-1-sec.-propyl-5-phenyl-2H-1,4-benzo two

Azatropylidene-2-ketone

3-(N '-the L-alanyl) amino-1,3-dihydro-1-propyl group-5-phenyl-2H-1,4-benzodiazepine

Assorted -2-ketone

3-(N '-the L-alanyl) amino-1,3-dihydro-1-cyclopropyl methyl-5-phenyl-2H-1,4-benzene

And diaza -2-ketone

3-(N '-the L-alanyl) amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodiazepine

Assorted -2-ketone.

Embodiment 8-M

3-(N '-the L-alanyl) amino-1-methyl-5-phenyl-1,3,4, the 5-tetrahydrochysene-

2H-1,5-benzodiazepine -2-ketone synthetic

Steps A: according to universal method 8-I, make 1,3,4,5-tetrahydrochysene-5-phenyl-2H-1,5-benzodiazepine -2-ketone (CAS No.32900-17-7) methylates, and obtains 1-methyl-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -2-ketone.

Step B: according to universal method 8-E and 8-F, with the product of steps A, preparation 3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydrochysene-2H-1,5-benzodiazepine -2-ketone.

Step C: adopt universal method III-D; make product and N-Boc-L-L-Ala (Sigma) coupling of step B; subsequently according to universal method 8-N; remove the Boc group; obtain 3-(N '-L-alanyl) amino-1-methyl-5-phenyl-1,3,4; 5-tetrahydrochysene-2H-1,5-benzodiazepine -2-ketone.

Embodiment 8-N

3-(N '-the L-alanyl) amino-2,4-dioxo-1-methyl-5-phenyl-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

Adopt universal method III-D, make 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.131604-75-6) and N-Boc-L-L-Ala (Sigma) coupling, according to universal method 8-N, remove the Boc group subsequently, obtain title compound.

Embodiment 8-O

3-((R)-diazanyl propionyl) amino-2,3-dihydro-1-methyl-5-phenyl)-

1H-1,4-benzodiazepine -2-ketone synthetic

Adopt universal method III-D, make 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone with (R)-N, N '-two-BOC-2-hydrazinepropionic acid (embodiment N) coupling.Adopt universal method 5-B to remove the Boc group, obtain title compound.

Embodiment 8-P

3-amino-2,4-dioxo-1,5-pair-(1-methylethyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

Steps A: 2,4-dioxo-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to Claremon, D.A. etc. apply for method described in the WO 96-US8400 960603 at PCT, by 1, and 2-phenylenediamine (Aldrich) and propanedioic acid (Aldrich), preparation 2,4-dioxo-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.49799-48-6).

Step B:2,4-dioxo-1,5-pair-(1-methylethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzene

And diaza 's is synthetic

According to universal method 8-M, with the product and 2-iodo propane (Aldrich) preparation 2 of steps A, 4-dioxo-1,5-couple-(1-methylethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.113021-84-4).Through flash chromatography (with ethyl acetate/hexane 3: 7 to 1: 1 gradient elutions), recrystallization purifying from ethyl acetate/hexane subsequently.

Step C:3-azido--2,4-dioxo-1,5-pair-(1-methylethyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-K, with the product of step B, be prepared as the 3-azido--2 of white solid, 4-dioxo-1,5-couple-(1-methylethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.186490-50-6).This product through the flash chromatography purifying, with hexane/ethyl acetate (4: 1) wash-out, is obtained 23: 1 mixture of false upright (pseudo-axial)/false calm (psedo-equatorial) trinitride.The false upright trinitride of pure product is used for next step.

Step D:3-amino-2,4-dioxo-1,5-pair-(1-methylethyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-L, with the product of step C, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-(1-methylethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.186490-51-7).Through the flash chromatography purifying, with methylene chloride (98: 2 to 95: 5 gradient elutions).By in toluene, be heated to 100-105 ℃ 15 minutes, the upright amine atropisomer of isolating vacation is converted into false calm amine atropisomer fully, the calm amine atropisomer of vacation is used for next step.At CDCl ₃Middle warp ¹H-NMR distinguishes isomer.Select ¹H-NMR (CDCl ₃): false upright amine 4.40 (s, 1H); False calm amine 3.96 (s, 1H).

Embodiment 8-Q 3-(R-2-thienyl glycyl) amino-2,4-dioxo-1,5-pair-(1-methylethyl)-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Synthesizing of steps A: N-(tert-butyl ester base)-R-2-thienyl glycine

According to Bodansky, M. etc. are at The Practice of Peptide Synthesis; SpringerVerlag; 1994 the 17th pages of described methods, by L-α-(2-thienyl) glycine (Simga), preparation N-(tert-butyl ester base)-R-2-thienyl glycine (CAS No.74462-03-1).

Step B:3-[N '-(tert-butyl ester base)-R-2-thienyl glycyl] amino-2, the 4-dioxo

-1,5-pair-(1-methylethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-J; with the product of embodiment 8-P and the product of above-mentioned steps A; be prepared as 3-[N '-(tert-butyl ester base)-R-2-thienyl glycyl of white foam shape thing] amino-2; 4-dioxo-1; 5-pair-(1-methylethyl)-2,3,4; 5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (9: 1 to 5: 1) gradient elution.

Step C:3-(R-2-thienyl glycyl) amino-2,4-dioxo-1,5-pair-(1-first

The base ethyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

According to above-mentioned universal method 8-N,, be prepared as the title compound of white solid with the product that derives from step B.

Embodiment 8-R

3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-methyl-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 2,4-dioxo-1,5-pair-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine

's is synthetic

According to universal method 8-M, with 2 of product that derives from embodiment 8-P steps A and methyl iodide (Aldrich) preparation, 4-dioxo-1,5-couple-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine (CAS No.23954-54-3).After the processing, when the partial concentration reactant, white solid product is precipitated out, and separates after filtration.

Step B:3-azido--2,4-dioxo-1,5-couple-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-

Benzodiazepine 's is synthetic

When preparing this material, universal method 8-K is improved with following method.At first the product of steps A is suspended among (non-solution) THF in-78 ℃, adds KN (TMS) subsequently ₂Solution, with making the suspension temperature to-35 ℃ in 12 minutes, suspension becomes solution in this process, is cooled to-78 ℃ again, handles according to universal method then.Through flash chromatography purifying 3-azido--2,4-dioxo-1,5-is two-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine with chloroform/ethyl acetate (7: 1) wash-out, grinds from hot chloroform and hexane then and is cooled to-23 ℃.Be separated into the product of white solid.

Step C:3-amino-2,4-dioxo-1,5-couple-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-

Benzodiazepine 's is synthetic

According to universal method 8-L, with the product that derives from step B, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .This crude product product uses without being further purified.

Step D:3-[N '-(tert-butyl ester base)-L-alanyl]-amino-2,4-dioxo-1,5-

Two-methyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-I; with N-Boc-L-L-Ala (Novabiochem) with derive from the product of step C; be prepared as 3-[N '-(tert-butyl ester base)-L-alanyl of white foam shape thing]-amino-2; 4-dioxo-1; 5-pair-methyl-2,3,4; 5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (2: 1 to 1: 1) gradient elution.

Step e: 3-(L-alanyl)-amino-2,4-dioxo-1,5-couple-methyl-2,3,4,5-

Tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

According to above-mentioned universal method 8-N,, be prepared as the title compound of canescence amorphous solid with the product that derives from step D.

Embodiment 8-S

3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(2-methyl-propyl)-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 2,4-dioxo-1,5-pair-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzene

And diaza 's is synthetic

According to universal method 8-M, with the product and the 1-iodo-2-methylpropane (Aldrich) that derive from embodiment 8-P steps A, preparation 2,4-dioxo-1,5-couple-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through flash chromatography (with 3: 7 to 1: 1 gradient elution of ethyl acetate/hexane), recrystallization purifying from ethyl acetate/hexane subsequently.

Step B:3-azido--2,4-dioxo-1,5-pair-(2-methyl-propyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

(adding KN (TMS) according to universal method 8-K ₂Formation precipitation in the process, but after adding the trisyl trinitride, dissolve), with the product that derives from steps A, be prepared as the 3-azido--2 of white solid, 4-dioxo-1,5-couple-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .This product is through with the flash chromatography of hexane/ethyl acetate (4: 1) wash-out with dichloromethane/hexane/ethyl acetate (10: 10: 1-8: the flash chromatography purifying second time 6: 1 gradient).

Step C:3-amino-2,4-dioxo-1,5-pair-(2-methyl-propyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-L, with the product that derives from step B, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with methylene chloride (98: 2 to 95: 5 gradient elutions contain 5% ammonia in methyl alcohol).

Step D:3-[N '-(tert-butyl ester base)-L-alanyl]-amino-2,4-dioxo-1,5-

Two-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-I; with N-Boc-L-L-Ala (Novabiochem) with derive from the product of step C; be prepared as 3-[N '-(tert-butyl ester base)-L-alanyl of white foam shape thing]-amino-2; 4-dioxo-1; 5-pair-(2-methyl-propyl)-2,3,4; 5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (3: 1 to 3: 2) gradient elution.

Step e: 3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(2-methyl-prop

Base)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

According to above-mentioned universal method 8-N,, be prepared as the title compound of white amorphous solid with the product that derives from step D.

Embodiment 8-T

3-(S-phenyl glycyl)-amino-2,4-dioxo-1,5-pair-(2-methyl-propyl)-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 3-[N '-(tert-butyl ester base)-S-phenyl glycyl]-amino-2,4-dioxo-1,5-pair-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-J; product and Boc-L-phenylglycocoll (Novabiochem with embodiment 8-S step C; CAS No.2900-27-8); be prepared as 3-[N '-(tert-butyl ester base)-S-phenyl glycyl of white foam shape thing]-amino-2,4-dioxo-1,5-pair-(2-methyl-propyl)-2; 3; 4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (9: 1 to 5: 1) gradient elution.

Step B:3-(S-phenyl glycyl)-amino-2,4-dioxo-1,5-pair-(2-methyl-prop

Base)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

According to above-mentioned universal method 8-N, with the product that derives from steps A, be prepared as 3-(S-phenyl the glycyl)-amino-2 of pale solid, 4-dioxo-1,5-pair-(2-methyl-propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride.

Embodiment 8-U

3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(cyclopropyl methyl)-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 2,4-dioxo-1,5-pair-(cyclopropyl methyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzene

And diaza 's is synthetic

According to universal method 8-M, with the product that derives from embodiment 8-P steps A and (bromomethyl) cyclopropane (Lancaster), preparation 2,4-dioxo-1,5-couple-(cyclopropyl methyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through flash chromatography (with ethyl acetate/hexane 3: 7 to the pure ethyl acetate gradient elution), recrystallization purifying from ethyl acetate/hexane subsequently.

Step B:3-azido--2,4-dioxo-1,5-pair-(cyclopropyl methyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

When preparing this material, universal method 8-K is improved with following method.At first the product of steps A is suspended among (non-solution) THF in-78 ℃, is adding KN (TMS) ₂Behind the solution, make the suspension temperature to-30 ℃, suspension becomes solution in this process, is cooled to-78 ℃ again.Be cooled in-78 ℃ of processes, precipitation begins to form again, and the temperature section that therefore contains the reaction flask of mixture is higher than cooling bath, rises to-50 ℃ to internal temperature, adds the trisyl azide solution then.Remove cooling bath, make the mixture temperature to-20 ℃, this moment, mixture almost became the solution of homogeneous, added acetate.Handle according to universal method then.Grind purifying 3-azido--2,4-dioxo-1,5-pair-(cyclopropyl methyl)-2 with heat to the ethyl acetate of room temperature, 3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine , then from heat recrystallization purifying to chloroform/ethyl acetate/ethanol (5: 5: 1) of-23 ℃, the separation white solid.

Step C:3-amino-2,4-dioxo-1,5-pair-(cyclopropyl methyl)-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-L, with the product that derives from step B, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-(cyclopropyl methyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through flash chromatography, with methylene chloride (98: 2 to 95: 5 gradient elutions contain 5% ammonia in methyl alcohol), recrystallization purifying from warm dichloromethane/hexane (1: 1) subsequently.

Step D:3-[N '-(tert-butyl ester base)-L-alanyl]-amino-2,4-dioxo-1,5-

Two-(cyclopropyl methyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-I; with N-Boc-L-L-Ala (Novabiochem) with derive from the product of step C; be prepared as 3-[N '-(tert-butyl ester base)-L-alanyl of white foam shape thing]-amino-2; 4-dioxo-1; 5-pair-(cyclopropyl methyl)-2,3,4; 5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (3: 1 to 2: 1) gradient elution.

Step e: 3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(cyclopropyl first

Base)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

According to above-mentioned universal method 8-N,, be prepared as the title compound of pale solid with the product that derives from step D.

Embodiment 8-V

3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-

2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 2,4-dioxo-1,5-couple-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-

Benzodiazepine 's is synthetic

Under room temperature, to embodiment 8-P steps A product (1.0eq., add in DMSO 17.08g) (500ml) stirred suspension neopentyl iodide (43.01g, 2.24eq., Aldrich) and cesium carbonate (72.65g, 2.3eq., Aldrich).With the mixture heating up to 75 that produces ℃ 30 minutes, and then (31.59g 1.0eq.), in 75 ℃, stirred this mixture 6 hours fast to add cesium carbonate.Cool off this mixture, add entry (500ml) and ethyl acetate (1000ml).Separate two-phase, water (1 * 500ml), the 1M aqueous hydrochloric acid (2 * 500ml) and salt solution (1 * 500ml) washs organic phase.Use the dried over mgso organic phase then, filter, concentrate and through the flash chromatography purifying, with hexane/ethyl acetate (3: 2 to 2: 3 gradient elutions), obtain being 2 of white solid, 4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .

Step B:3-azido--2,4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2,3,4,5-four

Hydrogen-1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-K, with the product of steps A, be prepared as the 3-azido--2 of white solid, 4-dioxo-1,5-couple-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .This product with hexanes/ch/ethyl acetate (10: 5: 1 to 5: 5: 1 gradient elutions), obtains 13: 1 separable mixture of uprightly false/false calm trinitride through the flash chromatography purifying.The false upright trinitride of pure product is used for next step.Select ¹H-NMR (CDCl ₃): false upright trinitride 5.12 (s, 1H); False calm trinitride 4.03 (s, 1H).

Step C:3-amino-2,4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2,3,4,5-four

Hydrogen-1H-1,5-benzodiazepine 's is synthetic

According to universal method 8-L, with the product that derives from step B, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through flash chromatography, with methylene chloride (98: 2 to 95: 5 gradient elutions contain 5% ammonia in methyl alcohol) purifying.Warp ¹H-NMR identifies about 4: 1 mixture of isolating white solid product for uprightly false and false calm amine atropisomer.With this mixture in toluene, be heated to 100 ℃ 20 minutes, and then concentrate and to obtain the false calm amine atropisomer of pure product, be white solid, use it for next step.Select ¹H-NMR (CDCl ₃): false upright amine 4.59 (s, 1H); False calm amine 4.03 (s, 1H).

Step D:3-[N '-(tert-butyl ester base)-L-alanyl]-amino-2,4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-I; with N-Boc-L-L-Ala (Novabiochem) with derive from the product of step C; be prepared as 3-[N '-(tert-butyl ester base)-L-alanyl of white foam shape thing]-amino-2; 4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2; 3; 4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (4: 1 to 5: 2) gradient elution.

Step e: 3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-(2, the 2-dimethyl propylene

Base)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Embodiment 8-W

3-(L-alanyl)-amino-2,4-dioxo-1,5-pair-phenyl-2,3,4, the 5-tetrahydrochysene-

1H-1,5-benzodiazepine hydrochloride synthetic

Steps A: 2,4-dioxo-1,5-pair-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine

's is synthetic

This method is Chan, and D.M.T. is at Tetrahedron Lett.1996,37, and the improving one's methods of method described in the 9013-9016.Under room temperature, nitrogen, with derive from embodiment 8-P steps A product (1.0eq., 7.50g), Ph ₃Bi (2.2eq., 41.26g, Aldrich), Cu (OAc) ₂(2.0eq., 15.48g, Aldrich), Et ₃(2.0eq., the mixed solution in methylene dichloride 8.62g) (100ml) stir 6 days (through the TLC monitoring) to N.Filter the removal solid by Celite pad, with methylene chloride (3 * 75ml) flushings.Concentrated filtrate is dissolved in it in hot methylene chloride (9: 1), filters by big silica gel stick harness, the usefulness methylene chloride (9: 1,2L) wash-out.Concentrated filtrate, residue be through the flash chromatography purifying, with absolute dichloromethane to methylene chloride (9: 1) gradient elution.When the component that contains product concentrates, 2,4-dioxo-1,5-pair-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine crystallizes out, and filtering separation is a white solid.

Step B:3-azido--2,4-dioxo-1,5-couple-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-

Benzodiazepine 's is synthetic

When preparing this material, universal method 8-K is improved with following method.At first the product with steps A is suspended among (non-solution) THF adding KN (TMS) in-70 ℃ ₂Behind the solution, with making the suspension temperature to-20 ℃ in 10 minutes, suspension becomes solution in this process, is cooled to-70 ℃ again.Handle according to universal method then.Grind the purifying title compound with hot chloroform/hexane (1: 1), obtain 3-azido--2,4-dioxo-1,5-pair-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine is white solid.

Step C:3-amino-2,4-dioxo-1,5-couple-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-

Benzodiazepine 's is synthetic

According to universal method 8-L, with the product that derives from step B, be prepared as the 3-amino-2 of white solid, 4-dioxo-1,5-couple-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with methylene chloride (98: 2 to 95: 5 gradients contain 5% ammonia in the methyl alcohol) wash-out.

Step D:3-[N '-(tert-butyl ester base)-L-alanyl]-amino-2,4-dioxo-1,5-

Two-phenyl-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-I; with N-Boc-L-L-Ala (Novabiochem) with derive from the product of step C; be prepared as 3-[N '-(tert-butyl ester base)-L-alanyl of white foam shape thing]-amino-2; 4-dioxo-1; 5-pair-phenyl-2,3,4; 5-tetrahydrochysene-1H-1,5-benzodiazepine .Through the flash chromatography purifying, with dichloromethane/ethyl acetate (4: 1 to 3: 1) gradient elution.

Step e: 3-(L-alanyl)-amino-2,4-dioxo-1,5-couple-phenyl-2,3,4,5-

Tetrahydrochysene-1H-1,5-benzodiazepine hydrochloride synthetic

Embodiment 8-X 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone synthetic

According to R.G.Sherrill etc. at J.Org.Chem.1995,60, method described in the 730-734 with glacial acetic acid and HBr gas, prepares this title compound.

Embodiment 8-Y

3-(L-is valyl)-amino-2,3-dihydro-1-methyl-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-[N '-(t-butyl carbamate)-L-is valyl]-amino-2,3-dihydro-1-

Methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone synthetic

By making (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1, it is free that 4-benzodiazepine -2-ketone, (1S)-7,7-dimethyl-2-oxo dicyclo [2.2.1] heptane-1-methanesulfonates (embodiment 8-B steps A) are allocated in methylene dichloride and the 1M salt of wormwood alkali.According to universal method III-D, make this unhindered amina and the coupling of N-Boc-Xie Ansuan then, obtain title compound.

C ₂₆H ₃₂N ₄O ₄(MW 464.62); Mass spectrum 464.3.

C ₂₆H ₃₂N ₄O ₄Analytical calculation value: C, 67.22; H, 6.94; N, 12.06.Measured value: C, 67.29; H, 6.79; N, 11.20.

Step B:3-(L-is valyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-

Synthesizing of benzodiazepine -2-ketone

C ₂₁H ₂₃N ₄O ₂(MW 363.48); Mass spectrum (M+H) 364.2.

Embodiment 8-Z

3-(L-tert-leucyl)-amino-2,3-dihydro-1-methyl-5-phenyl-

1H-1,4-benzodiazepine -2-ketone synthetic

Steps A: 3-[N '-(t-butyl carbamate)-L-tert-leucyl]-amino-2,3-two

Hydrogen-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone synthetic

By making (S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-ketone, (1S)-7, it is free that 7-dimethyl-2-oxo dicyclo [2.2.1] heptane-1-methanesulfonates (embodiment 8-B steps A) is allocated in methylene dichloride and the 1M salt of wormwood alkali.According to universal method III-D, make this unhindered amina and the coupling of N-Boc-tert-leucine then, obtain title compound.

C ₂₇H ₃₅N ₄O ₄(MW479.66); Mass spectrum 479.

Step B:3-(L-tert-leucyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-

1,4-benzodiazepine -2-ketone synthetic

According to universal method 8-C, use 3-[N '-(t-butyl carbamate)-L-tert-leucyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine -2-ketone is prepared as the title compound of white foam shape thing.

C ₂₂H ₂₅N ₄O ₂0.5H ₂O analytical calculation value: C, 68.19; H, 7.02; N, 14.40.Measured value: C, 68.24; H, 7.00; N, 14.00.

Embodiment 8-AA

3-(L-alanyl)-amino-2,3-dihydro-1, the 5-dimethyl-

1H-1,4-benzodiazepine 's is synthetic

According to universal method 8-I (using methyl-iodide), 8-D and 8-F, preparation 2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine .Make this intermediate and Boc-L-L-Ala (Novo) coupling according to universal method III-D, subsequently according to universal method 5-B go the protection, obtain title compound, with it without being further purified use.

Embodiment 8-AB

3-(L-3-thienyl glycyl)-amino-2,4-dioxo-1,5-pair-

(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

Synthesizing of steps A: N-(tert-butyl ester base)-L-3-thienyl glycine

According to Bodansky, M. etc. are at The Practice of Peptide Synthesis; SpringerVerlag; 1994 the 17th pages of described methods, by L-α-(3-thienyl) glycine (Simga), preparation N-(tert-butyl ester base)-L-3-thienyl glycine.

Step B:3-[N '-(tert-butyl ester base)-L-3-thienyl glycyl]-amino-

2,4-dioxo-1,5-couple-(2, the 2-dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-

1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method III-D; with the product of embodiment 8-V step C and the product of above-mentioned steps A; preparation 3-[N '-(tert-butyl ester base)-L-3-thienyl glycyl]-amino-2; 4-dioxo-1,5-pair-(2, the 2-dimethyl propyl)-2; 3; 4,5-tetrahydrochysene-1H-1,5-benzodiazepine .

Step C:3-(L-3-thienyl glycyl) amino-2,4-dioxo-1,5-pair-(2,2-

Dimethyl propyl)-2,3,4,5-tetrahydrochysene-1H-1,5-benzodiazepine 's is synthetic

According to above-mentioned universal method 8-N, with the product that derives from step B, the preparation title compound.

Embodiment B io-1

Be used to detect the cell screening of the inhibitor that amyloid beta produces

In clone, measure above-mentioned multiple formula I compound, suppress the ability that amyloid beta produces to estimate them with Swedish sudden change.Cell (K293=human kidney cells system) is used in this screening assay, and this clone is according to international application published number 94/10569 ⁸With Citron etc. ¹²Described method is carried out stable transfection with this clone of gene pairs of amyloid precursor protein 751 (APP751), and described precursor protein has two sudden changes, promptly by Lys ₆₅₁Met ₆₅₂Sport Asn ₆₅₁Leu ₆₅₂(numbering of APP751).This sudden change is commonly called Swedish sudden change, with the cell of called after " 293 751 SWE " with every hole 2-4 * 10 ⁴The concentration of cell is seeded in each hole of Corning96-orifice plate, and DulbeccoShi minimum essential medium (Sigma, St.Louis, MO)+10% foetal calf serum are contained in each hole.For the ELISA result of (about 0.2-2.5ng/ml) acquisition amyloid beta in the setting-out line scope, the number of cell is very important.

In 37 ℃, in the incubator of 10% carbon dioxide balance after the overnight incubation, remove substratum, every hole adds substratum that 200 μ l contain formula I compound (medicine) and substitutes and carry out two hours pre-treatment, and as preceding culturing cell.Preparation medicine storage liquid makes in the medicine final concentration used when handling in 100% DMSO, and the concentration of dimethyl sulfoxide (DMSO) is no more than 0.5%, in fact is generally 0.1%.

After pre-treatment finishes, remove substratum once more, replace with the substratum that contains novel drugs, with cell incubation two hours again.After the processing, in room temperature, with 1200rpm, with culture plate on Beckman GPR centrifugal 5 minutes, with sedimentation cell fragment from conditioned medium.According to international application published number 94/10569 ⁸Described method, from each hole, get 100 μ l conditioned mediums or its proper diluent, be transferred to and use antibody 266[P.Seubert, Nature (1992) 359:325-327] wrap in advance in the elisa plate of quilt, this antibody is the antibody at the amino acid/11 3-28 of beta amyloid peptide, with above-mentioned plate in 4 ℃ of store overnight.At second day, use traget antibody 3D6[P.Seubert, Nature (1992) 359:325-327 at beta amyloid peptide amino acid/11-5] carry out ELISA mensuration, to detect the amount that beta amyloid peptide produces.

According to Hansen etc. ¹³The modification method of method is measured the cellulotoxic effect of described compound.The 3-(4,5-dimethylthiazole-2-yl)-2 that adds 25 μ l in the residual cell in tissue culturing plate, 5-phenylbenzene tetrazolium bromide (MTT) (Sigma, St.Louis, MO) storing solution (5mg/ml), to final concentration be 1mg/ml.In 37 ℃,, add isopyknic MTT lysis buffer (50% dimethyl formamide solution of 20%w/v sodium lauryl sulphate, pH 4.7) and stop cytoactive cell incubation 1 hour.Spend the night to obtain extraction fully in the room temperature jolting.UV at Molecular Device _MaxMicrotiter plate is read to measure OD on the plate instrument _562nmAnd OD _650nmDifference, as the index of cells survival rate.

The result of beta amyloid peptide ELISA is fitted to typical curve, and represent with the beta amyloid peptide of ng/ml.For carrying out Cytotoxic normalization method,, and represent with the per-cent of the results of comparison that do not contain medicine with the result of these results divided by MTT.All results are the mean value and the standard deviation of at least six replications.

Measure the inhibition activity that the detection test-compound produces beta amyloid peptide with this in cell.The result of this mensuration proves that compared with the control, formula I compound produces beta amyloid peptide has 30% inhibition at least.

Embodiment B io-2

Amyloid beta discharges and/or the synthetic body is interior suppresses

How this embodiment explanation detects compound of the present invention to suppressing in amyloid beta release and/or the synthetic body.In these experiments, use the PDAPP mouse [Games etc. (1995) Nature 373:523-527] at 3-4 monthly age.According to the difference of compound to be tested, usually compound is formulated as the concentration of 1-10mg/ml.Because the low deliquescent factor of these compounds, thus can in various solvents, prepare, as Semen Maydis oil (Safeway, South San Francisco, CA); 10% ethanol Semen Maydis oil; 2-hydroxypropyl-beta-cyclodextrin (Research Biochemicals International, Natick MA) and carboxymethyl cellulose (Sigma Chemical Co., St.Louis MO).

With the subcutaneous mouse medicines of giving of No. 26 pins, after 3 hours, suffocating through carbonic acid gas makes described animal euthanasia, with 1cc 25G 5/8 " tuberculin syringe/pin (scribble 0.5M EDTA solution, pH 8.0) carries out heart puncturing extracting blood.Blood is placed Becton-Dickinson vacuum (vacutainer) pipe that contains EDTA, in 5 ℃, centrifugal 15 minutes with 1500 * g.Take out mouse brain then, separate and cut cortex and hippocampus, place on ice.1. brain is measured

With the electronic pestle (Fisher of Kontes, Pittsburgh PA), with ice-cold guanidine damping fluid (5.0M Guanidinium hydrochloride, the 50mM Tris-HCl of each brain zone at 10 times of volumes, pH 8.0) in homogenate, be used for the hippocampus and the cortical tissue of enzyme-linked immunosorbent assay (ELISA) with preparation.Under room temperature, homogenate was shaken on universal stage 3-4 hour gently, store the quantitative of pending amyloid beta in-20 ℃.

With ice-cold casein damping fluid [0.25% casein, phosphate-buffered saline (PBS), 0.05% sodiumazide, 20 μ g/ml press down the enzyme peptide, 5mM EDTA, and pH 8.0,10 μ g/ml leupeptins] with 1: 10 dilution brain homogenate, therefore the final concentration of guanidine is reduced to 0.5M, then in 4 ℃, with 16,000 * g centrifugal 20 minutes.If desired, the casein damping fluid that has the 0.5M Guanidinium hydrochloride by adding further dilutes sample, to reach the suitableeest scope that ELISA measures.Preparation amyloid beta standard substance (a 1-40 or 1-42 amino acid) make and form the 0.5M guanidine that is equivalent to contain 0.1% bovine serum albumin (BSA) eventually.

Total amyloid beta sandwich ELISA contains two kinds of monoclonal antibodies (mAb) of amyloid beta, and this sandwich ELISA is amyloid beta (aa 1-40) and amyloid beta (aa 1-42) quantitatively.Capture antibodies 266[P. Seubert, Nature (1992) 359:325-327] be the specific antibody of the amino acid/11 3-28 of amyloid beta.Antibody 3D6[Johnson-Wood etc., PNAS USA (1997) 94:1550-1555] be the specific antibody of the amino acid/11-5 of amyloid beta, with its biotinylation, in mensuration with the antibody of giving a report.The biotinylated method of 3D6 according to manufacturer [Pierce, Rockford IL] about the biotin labeled method of the NHS-of immunoglobulin (Ig), but with the pH of 100mM sodium bicarbonate be 8.5 damping fluid.The precursor protein (APP) of 3D6 antibody nonrecognition excretory amyloid or the APP of total length have the amyloid beta class of N-terminal aspartic acid and only detect.The susceptibility lower limit of this mensuration is about 50pg/ml (11pM), to the concentration of 1ng/ml endogenous mouse beta amyloid peptide is not shown cross reactivity at height.

Quantitatively the sandwich ELISA configuration of amyloid beta (aa 1-42) level uses as the mAb 21F12[Johnson-Wood of capture antibodies etc., PNAS USA (1997) 94:1550-1555] (the amino acid 33-42 of its identification amyloid beta).The biotinylated 3D6 that uses in this mensuration also is a report antibody, and the susceptibility lower limit is about 125pg/ml (28pM).

Under room temperature, with 266 and 21F12 catch mAbs and in 96 hole immunization test boards (Costar, Cambidge MA), spent the night with 10 μ g/mL bag.Content in the sucking-off orifice plate then, under room temperature, with the PBS damping fluid sealing of 0.25% human serum albumin at least 1 hour, then in 4 ℃, dry store down stand-by.Before usefulness, make orifice plate rehydrated with lavation buffer solution (Tris-buffer saline, 0.05%Tween 20).Sample and standard substance are added in the described orifice plate, be incubated overnight in 4 ℃.Between each step of measuring, all described plate is washed 3 times at least with lavation buffer solution.Under room temperature, with biotinylated 3D6 (being diluted to 0.5 μ g/ml) incubation 1 hour in each hole with casein incubation buffering liquid (0.05%Tween 20 for 0.25% casein, PBS, and pH 7.4).Under room temperature, will add in each hole 1 hour with the avidin-HRP (Vector, Burlingame CA) of dilution in 1: 4000 with the casein incubation buffer.(Pierce CambridgeMA), makes its reaction 15 minutes, adds 2N sulfuric acid then and stops enzyme reaction to add chromogenic substrate Slow TMB-ELISA.With MolecularDevices Vmax (Molecular Devices, Menlo Park CA), measure in the difference of 450nm and 650nm place optical density, so that reaction product is carried out quantitatively.2. blood measuring

Edta plasma is carried out dilution in 1: 1 in sample diluting liquid (0.2g/L sodium phosphate monohydrate (monoatomic base), 2.16g/L sodium phosphate heptahydrate (diacidic base), 0.5g/L Thiomersalate, 8.5g/L sodium-chlor, 0.5ml Triton X-405,6.0/L do not contain the bovine serum albumin and the water of sphaeroprotein).Adopt method described in the above-mentioned brain mensuration,, but replace described casein diluent with sample diluting liquid with sample and the standard substance in total amyloid beta mensuration (266 seizure/3D6 report antibody) working sample diluent.

Also can use non-above-mentioned preparation to be used for mammiferous oral administration and intravenously administrable.During oral administration, described compound and 100% Semen Maydis oil or the solution that contains 80% Semen Maydis oil, 19.5% oleic acid and 0.5%labrafil are mixed.Described compound is mixed with the concentration of 1mg/ml-10mg/ml with above-mentioned solution.Described compound solution preferably gives Mammals with the dosage per os of per kilogram of body weight 5ml.During intravenously administrable, preferably described compound is mixed with 3% ethanol, 3%solutol HS-15 and 94% brinish solution.Described compound preferably mixes with above-mentioned solution with the concentration of 0.25mg/ml-5mg/ml.The dosage that vein gives mammiferous compound solution is preferably per kilogram of body weight 2ml.

According to above-mentioned description, those skilled in the art can carry out various modifications and change to described composition and method.All are revised all in the scope that appending claims comprises.

Claims

1. beta amyloid peptide discharges and/or its synthetic method in the inhibition cell, this method comprises a kind of compound of the significant quantity that gives this cell inhibition cell release and/or synthesize beta amyloid peptide or the mixture of compound, and wherein said compound is represented by formula I:

A-B-C

Wherein A is selected from:

Z is selected from:

Hydrogen, hydroxyl or fluorine, or X ' and X " form oxo base together;

M is 0 or 1 integer, and

P is 0 or 1 integer;

And another prerequisite is that when W was oxygen, X was not an oxygen;

B is selected from:

And another prerequisite is that when W was oxygen, X was not an oxygen;

C is selected from: (i)-C (O) Y or-C (S) Y

Wherein Y is selected from:

(a) alkyl or cycloalkyl,

(c) alkoxyl group or thio alkoxy,

(d) substituted alkoxy or replacement thio alkoxy,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic radical,

(i)-NR ' R "; wherein R ' and R " be independently selected from hydrogen, alkyl, alkenyl, alkynyl group, substituted alkyl, the substituted alkenyl base, the substituted alkenyl base, cycloalkyl, aryl, heteroaryl, heterocyclic radical, wherein R ' or R " one of be hydroxyl or alkoxyl group; and R ' and R " in conjunction with forming a cyclic group, described cyclic group has 2-8 carbon atom, can randomly contain 1-2 other be selected from oxygen, the heteroatoms of sulphur and nitrogen, and can randomly use one or more alkyl, alkoxyl group or carboxyalkyl replace

Wherein A forms heterocyclic radical with-C=N=, this heterocyclic radical can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, each in this ring structure can randomly replace with being selected from following 1-4 substituting group again: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, aryl, heteroaryl, heterocyclic radical,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N, N-two replaces alkylamino, the N-alkenyl amino, N, N-two alkenyl aminos, N-substituted alkenyl base amino, N, N-two substituted alkenyl base amino, the N-naphthene amino, N, N-two naphthene aminos, N-substituted ring alkylamino, N, N-two substituted ring alkylaminos, the N-virtue is amino, N, the N-diarylamino, N-is assorted, and virtue is amino, N, N-two assorted virtues are amino, N-heterocyclic radical amino, N, amino and the mixing N of N-two heterocyclic radicals, N-amino, described mixing N, N-amino comprises one first substituting group and one on described amino disubstituted, described substituting group is selected from alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical, prerequisite are that described first and second substituting groups are inequality;

Other prerequisite is,

A. work as A and have structure (i), wherein R ¹Be phenyl, Z is-CH ₂OC (O)-, R ²Be methyl, and p is 0, B has structure (iii), and wherein W is-NH-, and X is-CH ₂-, and R ⁴During for benzyl, C is not-C (O) OCH ₃

B. work as A and have structure (i), wherein R ¹Be 3, the 5-difluorophenyl, Z is-CH ₂C (O)-, R ²Be methyl, p is 0, and B has structure (ii), and wherein W is＞NC (O) OC (CH ₃) ₃, X is-CH ₂-, R ⁴Be phenyl, then C is not-C (O) OCH ₃And

2. prevent the method for the patient AD outbreak of development AD risk, this method comprises and gives described patient a kind of medicinal compositions that said composition comprises pharmaceutically inert carrier and the formula I compound of significant quantity or the mixture of formula I compound:

A-B-C

Wherein A is selected from:

Z is selected from:

Hydrogen, hydroxyl or fluorine, or X ' and X " form oxo base together;

M is 0 or 1 integer, and

P is 0 or 1 integer;

And another prerequisite is that when W was oxygen, X was not an oxygen;

B is selected from:

And another prerequisite is that when W was oxygen, X was not an oxygen;

C is selected from:

(i)-C (O) Y or-C (S) Y

Wherein Y is selected from:

(a) alkyl or cycloalkyl,

(c) alkoxyl group or thio alkoxy,

(d) substituted alkoxy or replacement thio alkoxy,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic radical,

Wherein A forms heterocyclic radical with-C=N=, this heterocyclic radical can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, each in this ring structure can randomly replace with the substituting group that is selected from following 1-4 again: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, aryl, heteroaryl, heterocyclic radical,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N, N-two replaces alkylamino, the N-alkenyl amino, N, N-two alkenyl aminos, N-substituted alkenyl base amino, N, N-two substituted alkenyl base amino, the N-naphthene amino, N, N-two naphthene aminos, N-substituted ring alkylamino, N, N-two substituted ring alkylaminos, the N-virtue is amino, N, the N-diarylamino, N-is assorted, and virtue is amino, N, N-two assorted virtues are amino, N-heterocyclic radical amino, N, amino and the mixing N of N-two heterocyclic radicals, N-amino, described mixing N, N-amino comprises one first substituting group and one on described amino disubstituted, described substituting group is selected from alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical, prerequisite are that described first and second substituting groups are inequality;

Prerequisite is to have structure (i) as A, and B is when having structure (i), and then C does not have structure (i) or (ii);

Other prerequisite is,

A. work as A and have structure (i), wherein R ¹Be phenyl, Z is-CH ₂OC (O)-, R ₂Be methyl, and p is 0, B has structure (iii), and W is-NH-that X is-CH ₂-, and R ⁴During for benzyl, C is not-C (O) OCH ₃

B. work as A and have structure (i), wherein R ¹Be 3, the 5-difluorophenyl, Z is-CH ₂C (O)-, R ₂Be methyl, and p is 0, B has structure (ii), and wherein W is＞NC (O) OC (CH ₃) ₃, X is-CH ₂-, and R ⁴During for phenyl, then C is not-C (O) OCH ₃And

3. treatment suffers from the patient of AD so that suppress the method that this patient's state of an illness further worsens, this method comprises and gives described patient a kind of medicinal compositions that this medicinal compositions comprises pharmaceutically inert carrier and the formula I compound of significant quantity or the mixture of formula I compound:

A-B-C

Wherein A is selected from:

Z is selected from:

Hydrogen, hydroxyl or fluorine, or X ' and X " form the oxo base together;

M is 0 or 1 integer, and

P is 0 or 1 integer;

And another prerequisite is that when W was oxygen, X was not an oxygen;

B is selected from:

And another prerequisite is that when W was oxygen, X was not an oxygen;

C is selected from: (i)-C (O) Y or-C (S) Y

Wherein Y is selected from:

(a) alkyl or cycloalkyl,

(c) alkoxyl group or thio alkoxy,

(d) substituted alkoxy or replacement thio alkoxy,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic radical,

(l)-ONR ⁹[C (O) O] _zR ¹⁰, wherein z is 0 or 1, R ⁹And R ¹⁰As above-mentioned definition;

(ii)????????-CR ¹¹R ¹¹Y’

Other prerequisite is,

A. work as A and have structure (i), R ¹Be phenyl, Z is-CH ₂OC (O)-, R ₂Be methyl, and p is 0, B has structure (iii), and wherein W is-NH-, and X is-CH ₂-, and R ⁴During for benzyl, C is not-C (O) OCH ₃

4. according to claim 1,2 or 3 method, its Chinese style I compound is also characterized by Formula Il:

5. according to the method for claim 4, wherein m is 1, and Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, or X ' and X " oxo base of formation.

6. according to the method for claim 5, R wherein ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

7. according to the method for claim 5, R wherein ¹For being selected from the substituted aryl of monosubstituted phenyl, di-substituted-phenyl and tri-substituted phenyl.

8. according to the method for claim 7, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

9. according to the method for claim 4, R wherein ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

10. according to the method for claim 4, R wherein ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

11. according to the method for claim 10, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

12. according to the method for claim 4, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

13. according to the method for claim 4, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃

14. according to the method for claim 4, wherein R ⁵And R ⁶Substituting group be independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

15. according to the method for claim 4, wherein

Group is also characterized by following heterocycle structure:

16. according to the method for claim 15, wherein said heterocycle structure is selected from the 3-methyl isophthalic acid, and 2,4-oxadiazole-5-base, thiazoline-2-base, 3-phenyl-1,2,4-oxadiazole-5-base and 3-(to methoxyl group-benzyl)-1,2,4-oxadiazole-5-base.

17. according to the method for claim 4, wherein said formula II compound is selected from:

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-3-methyl isophthalic acid, 2, the 4-oxadiazole;

(S)-and 5-[1-N-[N-(3,5-difluoro phenylacetyl)-L-alanyl] amino-1-phenyl] methyl-3-phenyl-1,2, the 4-oxadiazole; And

18. according to claim 1,2 or 3 method, wherein said formula I compound is also characterized by Formula Il I and IV:

With

19. according to the method for claim 18, wherein m is 1, Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, and X ' and X " oxo base of formation.

20. according to the method for claim 19, wherein R ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

21. according to the method for claim 19, wherein R ¹For being selected from the substituted aryl of monosubstituted phenyl, di-substituted-phenyl and tri-substituted phenyl.

22. according to the method for claim 21, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

23. according to the method for claim 18, wherein R ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

24. according to the method for claim 18, wherein R ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

25. according to the method for claim 24, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

26. according to the method for claim 18, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

27. according to the method for claim 18, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃

28. according to the method for claim 18, wherein R ⁴Be selected from hydrogen, methyl, phenyl and benzyl.

29. according to the method for claim 18, wherein R ⁶Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-.

30. according to the method for claim 18, wherein Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ".

31. according to the method for claim 30, wherein Y is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy, amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl (azetidino), N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (right-aminomethyl phenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂,-NHCH ₂-(tetrahydrofuran (THF)-2-yl) and-CH ₂CH ₂CH (CH ₃) ₂

32. according to the method for claim 18, wherein the heterocycle structure by W and X definition is selected from 4,5-thiazoline, 3,4-dihydro-1, the different diazole of 3-, 3, the 4-dihydro-different diazole of 3-N-tert.-butoxy-3-and 4,5-dihydro-oxazole.

33. according to the method for claim 18, wherein said formula II compound is selected from:

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-ethoxycarbonyl-2-thiazoline

2-[(S)-1-(3,5-dichlorobenzene amido) ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine

2-[1-(3,5-difluorophenyl kharophen)-1-phenyl] methyl-4-methoxycarbonyl-2-thiazoline; With

34. according to claim 1,2 or 3 method, wherein said formula I compound is also characterized by following formula V and VI:

35. according to the method for claim 34, wherein m is 1, Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, and X ' and X " oxo base of formation.

36. according to the method for claim 35, wherein R ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

37. according to the method for claim 35, wherein R ¹For being selected from the substituted aryl of monosubstituted phenyl, disubstituted phenyl and tri-substituted phenyl.

38. according to the method for claim 37, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

39. according to the method for claim 34, wherein R ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

40. according to the method for claim 34, wherein R ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

41. according to the method for claim 40, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

42. according to the method for claim 34, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

43. according to the method for claim 34, wherein R ⁴Be selected from hydrogen, methyl, phenyl and benzyl.

44. according to the method for claim 34, wherein R ⁶Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-.

45. according to the method for claim 34, wherein Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ".

46. according to the method for claim 45, wherein Y is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy, amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl, N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (p-methylphenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂-φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂With-NHCH ₂-(tetrahydrofuran (THF)-2-yl).

47. according to the method for claim 34, wherein the heterocycle structure by W and X definition is selected from 4,5-thiazoline, 3,4-dihydro-1, the different diazole of 3-, 3, the 4-dihydro-different diazole of 3-N-tert.-butoxy-3-and 4,5-dihydro-oxazole.

48. according to the method for claim 34, wherein said formula V and VI compound are selected from:

4-[N-(S)-(1-methoxycarbonyl-1-phenyl) methyl] carbamyl-2-(3,5-difluorophenyl methyl)-2-thiazoline; With

48. beta amyloid peptide discharges and/or its synthetic method in the inhibition cell, this method comprises a kind of compound of the significant quantity that gives this cell inhibition cell release and/or synthesize beta amyloid peptide or the mixture of compound, and wherein said compound is represented by formula VII and VIII:

With

R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W and X such as above-mentioned definition;

W ' and-C (H) _sC (=U)-together form cycloalkyl, cycloalkenyl group, heterocyclic radical, the cycloalkyl that replaces or the cycloalkenyl group of replacement, wherein said cycloalkyl, cycloalkenyl group, heterocyclic radical, each of the cycloalkyl that replaces or the cycloalkenyl group of replacement can be randomly be selected from following one or more ring structures and condense and form two and condense or many fused rings system (preferably no more than 5 fused rings): cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, in this ring structure each can randomly replace with being selected from following 1-4 substituting group again: hydroxyl, halo, alkoxyl group, substituted alkoxy, thio alkoxy, replace thio alkoxy, aryl, heteroaryl, heterocyclic radical, nitro, cyano group, carboxyl, carboxylicesters, alkyl, substituted alkyl, alkenyl, the substituted alkenyl base, alkynyl group, replace alkynyl group, amino, the N-alkylamino, N, the N-dialkylamino, N-replaces alkylamino, N-alkyl N-replaces alkylamino, N, N-two replaces alkylamino,-NHC (O) R ¹⁰,-NHSO ₂R ¹⁰,-C (O) NH ₂,-C (O) NHR ¹⁰,-C (O) NR ¹⁰R ¹⁰,-S (O) R ¹⁰,-S (O) ₂R ¹⁰,-S (O) ₂NHR ¹⁰With-S (O) ₂NR ¹⁰R ¹⁰, each R wherein ¹⁰Be independently selected from alkyl, substituted alkyl or aryl;

S is 0 or 1 integer; And

T is 0 or 1 integer.

49. prevent the method for the patient AD outbreak of development AD risk, this method comprises and give described patient a kind of medicinal compositions, said composition comprises pharmaceutically formula VII and a kind of compound of VIII or the mixture of compound of inert carrier and significant quantity:

S is 0 or 1 integer; And

T is 0 or 1 integer.

50. suffering from the patient of AD, treatment suppresses the method that this patient's state of an illness further worsens, this method comprises and gives described patient a kind of medicinal compositions, and this medicinal compositions comprises pharmaceutically formula VII and a kind of compound of VIII or the mixture of compound of inert carrier and significant quantity: R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W and X such as above-mentioned definition;

S is 0 or 1 integer; And

T is 0 or 1 integer.

51. formula I compound:

A-B-C

Wherein A is selected from:

Z is selected from:

Hydrogen, hydroxyl or fluorine, or X ' and X " form oxo base together;

M is 0 or 1 integer, and

P is 0 or 1 integer;

And another prerequisite is that when W was oxygen, X was not an oxygen;

B is selected from:

And another prerequisite is that when W was oxygen, X was not an oxygen;

C is selected from: (i)-C (O) Y or-C (S) Y

Wherein Y is selected from:

(a) alkyl or cycloalkyl,

(c) alkoxyl group or thio alkoxy,

(d) substituted alkoxy or replacement thio alkoxy,

(e) hydroxyl,

(f) aryl,

(g) heteroaryl,

(h) heterocyclic radical,

Each R wherein ¹¹Be independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic radical, and Y ' be selected from hydroxyl, alkoxyl group, amino, thiol, substituted alkoxy, thio alkoxy, replacement thio alkoxy ,-O (C) R ⁹,-SSR ⁹With-SSC (O) R ⁹, R wherein ⁹Be selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical; And

Other prerequisite is,

52. according to the compound of claim 51, its Chinese style I compound is also characterized by Formula Il:

R wherein ¹, R ², R ⁵, R ⁶, definition in A, Z, m and p such as the claim 51.

53. according to the compound of claim 52, wherein m is 1, Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, or X ' and X " oxo base of formation.

54. according to the compound of claim 52, wherein R ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

55. according to the compound of claim 52, wherein R ¹For being selected from the substituted aryl of monosubstituted phenyl, di-substituted-phenyl and tri-substituted phenyl.

56. according to the compound of claim 55, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

57. according to the compound of claim 52, wherein R ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

58. according to the compound of claim 52, wherein R ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

59. according to the compound of claim 58, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

60. according to the compound of claim 52, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

61. according to the compound of claim 52, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃

62. according to the compound of claim 52, wherein R ⁵And R ⁶Substituting group be independently selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

63. according to the compound of claim 52, wherein

Group is also characterized by following heterocycle structure:

64. according to the compound of claim 63, wherein said heterocycle structure is selected from the 3-methyl isophthalic acid, and 2,4-oxadiazole-5-base, thiazoline-2-base, 3-phenyl-1,2,4-oxadiazole-5-base and 3-(to methoxyl group-benzyl)-1,2,4-oxadiazole-5-base.

65. according to the compound of claim 52, wherein said formula II compound is selected from:

66. according to the compound of claim 51, wherein said formula I compound is also characterized by Formula Il I and IV:

R wherein ¹, R ², R ⁴, R ⁶, definition in W, X, Y, Z, m and p such as the claim 51.

67. according to the compound of claim 66, wherein m is 1, Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, and X ' and X " oxo base of formation.

68. according to the compound of claim 66, wherein R ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

69. according to the compound of claim 66, wherein R ¹For being selected from the substituted aryl of monosubstituted phenyl, di-substituted-phenyl and tri-substituted phenyl.

70. according to the compound of claim 69, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

71. according to the compound of claim 66, wherein R ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

72. according to the compound of claim 66, wherein R ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

73. according to the compound of claim 72, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

74. according to the compound of claim 66, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

75. according to the compound of claim 66, wherein R ²Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl and-CH ₂CH ₂SCH ₃

76. according to the compound of claim 66, wherein R ⁴Be selected from hydrogen, methyl, phenyl and benzyl.

77. according to the compound of claim 66, wherein R ⁶Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-.

78. according to the compound of claim 66, wherein Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ".

79. according to the compound of claim 78, wherein Y is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy, amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl (azetidino), N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (right-aminomethyl phenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ) ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂,-NHCH ₂-(tetrahydrofuran (THF)-2-yl) and-CH ₂CH ₂CH (CH ₃) ₂

80. according to the compound of claim 66, wherein the heterocycle structure by W and X definition is selected from 4,5-thiazoline, 3,4-dihydro-1, the different diazole of 3-, 3, the 4-dihydro-different diazole of 3-N-tert.-butoxy-3-and 4,5-dihydro-oxazole.

81. according to the compound of claim 66, wherein said formula II compound is selected from:

(S)-2-[1-(3,5-difluorophenyl kharophen) ethyl]-4-ethoxycarbonyl-2-thiazoline

2-[(S)-1-(3,5-dichlorobenzene amido) ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine

82. according to the compound of claim 51, wherein said formula I compound is also characterized by following formula V and VI: R wherein ¹, R ⁴, R ⁶, T ', X ', X ", definition in W, X and Y such as the claim 51.

83. according to the compound of claim 82, wherein m is 1, Z is-CX ' X " C (O)-, X " and be hydrogen, X ' is hydrogen or fluorine, and X ' and X " oxo base of formation.

84. according to the compound of claim 82, wherein R ¹For being selected from the unsubstituting aromatic yl of phenyl, 1-naphthyl and 2-naphthyl.

85. according to the compound of claim 82, wherein R ¹For being selected from the substituted aryl of monosubstituted phenyl, di-substituted-phenyl and tri-substituted phenyl.

86. according to the compound of claim 85, the R of wherein said replacement ¹Phenyl is selected from the 2-chloro-phenyl-, the 2-fluorophenyl, the 2-bromophenyl, the 2-hydroxy phenyl, the 2-nitrophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-Phenoxyphenyl, the 2-trifluoromethyl, the 4-fluorophenyl, the 4-chloro-phenyl-, the 4-bromophenyl, the 4-nitrophenyl, the 4-aminomethyl phenyl, the 4-hydroxy phenyl, the 4-p-methoxy-phenyl, the 4-ethoxyl phenenyl, the 4-butoxy phenyl, the 4-isopropyl phenyl, the 4-Phenoxyphenyl, the 4-trifluoromethyl, the 4-hydroxymethyl phenyl, the 3-p-methoxy-phenyl, the 3-hydroxy phenyl, the 3-nitrophenyl, the 3-fluorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-Phenoxyphenyl, 3-sulfo-p-methoxy-phenyl, the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, the 3-dichlorophenyl, 2, the 3-difluorophenyl, 2, the 4-dichlorophenyl, 2, the 5-Dimethoxyphenyl, 3, the 4-dichlorophenyl, 3, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-difluorophenyl, 3, the 5-dichlorophenyl, 3,5-two (trifluoromethyl) phenyl, 3, the 5-Dimethoxyphenyl, 2, the 4-dichlorophenyl, 2, the 4-difluorophenyl, 2, the 6-difluorophenyl, 3,4, the 5-trifluorophenyl, 3,4, the 5-trimethoxyphenyl, 3,4,5-three (trifluoromethyl) phenyl, 2,4, the 6-trifluorophenyl, 2,4, the 6-trimethylphenyl, 2,4,6-three (trifluoromethyl) phenyl, 2,3, the 5-trifluorophenyl, 2,4, the 5-trifluorophenyl, 2, the 5-difluorophenyl, 2-fluoro-3-trifluoromethyl, 4-fluoro-2-trifluoromethyl, 2-fluoro-4-trifluoromethyl, 4-benzyloxy phenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chloro-phenyl-, 2,3,4,5, the 6-pentafluorophenyl group, 2, the 5-3,5-dimethylphenyl, 4-phenyl and 2-fluoro-3-trifluoromethyl.

87. according to the compound of claim 82, wherein R ¹For being selected from the alkaryl of benzyl, 2-phenylethyl and 3-phenyl n-propyl.

88. according to the compound of claim 82, wherein R ¹Be selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl group.

89. according to the compound of claim 88, wherein R ¹Be selected from sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH=CH ₂,-CH ₂CH=CH (CH ₂) ₄CH ₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, hexamethylene-1-thiazolinyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂-cyclohexyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclohexyl and-CH ₂CH ₂-cyclopentyl.

90. according to the compound of claim 82, wherein R ¹Heteroaryl for heteroaryl or replacement, be selected from pyridine-2-base, pyridin-3-yl, pyridin-4-yl, fluorine pyridyl (comprising 5-fluorine pyridin-3-yl), chloropyridine base (comprising 5-chloropyridine-3-yl), thiophene-2-base, thiene-3-yl-, benzothiazole-4-base, 2-Ben base benzoxazole-5-base, furans-2-base, cumarone-2-base, benzo-thiophene-2-base, 2-chlorothiophene-5-base, 3-methyl-isoxazole-5-base, 2-(thienyl) thiophene-5-base, 6-methoxyl group benzo-thiophene-2-base, 3-phenyl-1,2,4-Liu Dai oxadiazole-5-base and 2-Ben Ji oxazole-4-base.

91. according to the compound of claim 82, wherein R ⁴Be selected from hydrogen, methyl, phenyl and benzyl.

92. according to the compound of claim 82, wherein R ⁶Be selected from hydrogen, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl ,-CH ₂CH (CH ₂CH ₃) ₂, 2-methyl-normal-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, suberyl, allyl group, isobutyl-2-thiazolinyl, 3-methyl amyl ,-CH ₂-cyclopropyl ,-CH ₂-cyclohexyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-indol-3-yl, to (phenyl) phenyl, adjacent fluorophenyl, a fluorophenyl, to fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, styroyl, benzyl, a hydroxybenzyl, to hydroxybenzyl, to nitrobenzyl, m-trifluoromethylphenyl, right-(CH ₃) ₂NCH ₂CH ₂CH ₂O-benzyl, right-(CH ₃) ₃COC (O) CH ₂O-benzyl, right-(HOOCCH ₂O)-benzyl, 2-aminopyridine-6-base, right-(N-morpholino-CH ₂CH ₂O)-benzyl ,-CH ₂CH ₂C (O) NH ₂,-CH ₂-imidazol-4 yl ,-CH ₂-(3-tetrahydrofuran base) ,-CH ₂-thiophene-2-base ,-CH ₂(1-methyl) cyclopropyl ,-CH ₂-thiene-3-yl-, thiene-3-yl-, thiophene-2-base ,-CH ₂-C (O) the O-tertiary butyl ,-CH ₂-C (CH ₃) ₃,-CH ₂CH (CH ₂CH ₃) ₂,-2-methylcyclopentyl ,-hexamethylene-2-thiazolinyl ,-CH[CH (CH ₃) ₂] COOCH ₃,-CH ₂CH ₂N (CH ₃) ₂,-CH ₂C (CH ₃)=CH ₂,-CH ₂CH=CHCH ₃(cis and trans) ,-CH ₂OH ,-CH (OH) CH ₃,-CH (the O-tertiary butyl) CH ₃,-CH ₂OCH ₃,-(CH ₂) ₄NH-Boc ,-(CH ₂) ₄NH ₂,-CH ₂-pyridyl (for example 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl) ,-CH ₂-naphthyl (for example 1-naphthyl and 2-naphthyl) ,-CH ₂-(N-morpholino), right-(N-morpholino-CH ₂CH ₂O)-benzyl, benzo [b] thiophene-2-base, 5-chlorobenzene [b] thiophene-2-base, 4,5,6 also, 7-tetrahydro benzo [b] thiophene-2-base, benzo [b] thiene-3-yl-, 5-chlorobenzene also [b] thiene-3-yl-, benzo [b] thiophene-5-base, 6-methoxynaphthalene-2-base ,-CH ₂CH ₂SCH ₃, thiophene-2-base, thiene-3-yl-etc.

93. according to the compound of claim 82, wherein Y be hydroxyl, alkoxyl group, substituted alkoxy and-NR ' R ".

94. according to the compound of claim 93, wherein Y is selected from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, neopentyl oxygen, benzyloxy, 2-phenyl ethoxy, 3-phenyl positive propoxy, 3-iodine positive propoxy, 4-bromine n-butoxy, amino (NH ₂) ,-NH (isobutyl-) ,-NH (sec-butyl), N-methylamino, N, N-dimethylamino, N-benzylamino, N-morpholino, azetidinyl, N-thiomorpholine generation, N-piperidyl, N-hexamethyleneimino, N-heptamethylene imino-, N-pyrrolidyl ,-the NH-methylallyl ,-NHCH ₂-(furans-2-yl) ,-NHCH ₂-cyclopropyl ,-NH (tertiary butyl) ,-NH (p-methylphenyl) ,-NHOCH ₃,-NHCH ₂(to fluorophenyl) ,-NHCH ₂CH ₂OCH ₃,-NH-cyclohexyl ,-NHCH ₂CH ₂N (CH ₃) ₂,-NHCH ₂C (CH ₃) ₃,-NHCH ₂-(pyridine-2-yl) ,-NHCH ₂-(pyridin-3-yl) ,-NHCH ₂-(pyridin-4-yl), N-thiazolidyl ,-N (CH ₂CH ₂CH ₃) ₂,-NHOH ,-NH (p-NO ₂-φ) ,-NHCH ₂(p-NO ₂-φ) ,-NHCH ₂(m-NO ₂-φ) ,-N (CH ₃) OCH ₃,-N (CH ₃) CH ₂-φ ,-NHCH ₂-(3, the 5-difluorophenyl) ,-NHCH ₂CH ₂F ,-NHCH ₂(p-CH ₃O-φ) ,-NHCH ₂(m-CH ₃O-φ) ,-NHCH ₂(p-CF ₃-φ) ,-N (CH ₃) CH ₂CH ₂OCH ₃,-NHCH ₂CH ₂-φ ,-NHCH (CH ₃) φ ,-NHCH ₂(p-F-φ) ,-N (CH ₃) CH ₂CH ₂N (CH ₃) ₂With-NHCH ₂-(tetrahydrofuran (THF)-2-yl).

95. according to the method for claim 82, wherein the heterocycle structure by W and X definition is selected from 4,5-thiazoline, 3,4-dihydro-1, the different diazole of 3-, 3, the 4-dihydro-different diazole of 3-N-tert.-butoxy-3-and 4,5-dihydro-oxazole.

96. according to the method for claim 82, wherein said formula V and VI compound are selected from:

97. the compound of formula VII and VIII: R wherein ¹, R ⁴, R ⁶, T ', X ', X ", W and X such as above-mentioned definition;

S is 0 or 1 integer; And

T is 0 or 1 integer.

98. the compound of formula IX and X:

S is 0 or 1 integer; And

T is 0 or 1 integer.

99. medicinal compositions, comprise pharmaceutically acceptable carrier and significant quantity according to each compound among the claim 51-98.